Clozapine - Wikipedia

Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors. Clozapine is an antagonist at the 5-HT2A ... Clozapine FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Typicalantipsychoticmedication Nottobeconfusedwithclonazepamorclonidine. ClozapineClinicaldataTradenamesClozaril,Leponex,Versacloz,others[1]AHFS/Drugs.comMonographMedlinePlusa691001Licensedata US DailyMed: Clozapine Pregnancycategory AU:C RoutesofadministrationBymouth,intramuscularinjectionDrugclassAtypicalantipsychoticATCcodeN05AH02(WHO)LegalstatusLegalstatus AU:S4(Prescriptiononly) US:℞-only[2] PharmacokineticdataBioavailability60to70%MetabolismLiver,byseveralCYPisozymesEliminationhalf-life4to26hours(meanvalue14.2hoursinsteadystateconditions)Excretion80%inmetabolizedstate:30%biliaryand50%kidneyIdentifiers IUPACname 8-Chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine CASNumber5786-21-0 YPubChemCID2818IUPHAR/BPS38DrugBankDB00363 YChemSpider10442628 YUNIIJ60AR2IKICKEGGD00283 YChEBICHEBI:3766 YChEMBLChEMBL42 YCompToxDashboard(EPA)DTXSID5022855ECHAInfoCard100.024.831ChemicalandphysicaldataFormulaC18H19ClN4Molarmass326.83 g·mol−13Dmodel(JSmol)InteractiveimageMeltingpoint183 °C(361 °F)Solubilityinwater0.1889[3] SMILES CN1CCN(CC1)C2=Nc3cc(ccc3Nc4c2cccc4)Cl InChI InChI=1S/C18H19ClN4/c1-22-8-10-23(11-9-22)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18/h2-7,12,20H,8-11H2,1H3 YKey:QZUDBNBUXVUHMW-UHFFFAOYSA-N Y   (verify) Clozapineisapsychiatricmedicationandisthefirstatypicalantipsychotic.[4]Itisprimarilyusedtotreatpeoplewithschizophreniaandschizoaffectivedisorderswhohavehadaninadequateresponsetootherantipsychoticsorwhohavebeenunabletotolerateotherdrugsduetoextrapyramidalsideeffects.ItisalsousedforthetreatmentofpsychosisinParkinson'sdisease.[5][6]Clozapineisregardedasthegold-standardtreatmentwhenothermedicationhasbeeninsufficientlyeffectiveanditsuseisrecommendedbymultipleinternationaltreatmentguidelines.[7][8][9][10][11][12][13] Theroleofclozapineintreatment-resistantschizophreniawasestablishedbythelandmarkClozarilCollaborativeStudyGroupStudy#30[14]inwhichclozapineshowedmarkedbenefitscomparedtochlorpromazineinagroupofpatientswithprotractedpsychosiswhohadalreadyshownaninadequateresponsetootherantipsychotics.[15]Whiletherearesignificantsideeffects,clozapineremainsthemosteffectivetreatmentwhenoneormoreotherantipsychoticshavehadaninadequateresponse.Theuseofclozapineisassociatedwithmultipleimprovedoutcomes,includingareducedrateofall-causemortality,suicideandhospitalization.[16][17]Inanetworkcomparativemeta-analysisof15antipsychoticdrugs,clozapinewasfoundtobesignificantlymoreeffectivethanallotherdrugs.[18]InanotherUKstudy,themajorityofpatients(over85%ofrespondents)whotookclozapinepreferredittotheirprevioustherapies,feltbetteronitandwantedtokeeptakingit.[19]InaCanadiansurveyof130patients,themajorityreportedbettersatisfaction,qualityoflife,compliancewithtreatment,thinking,mood,andalertness.[20] Comparedtootherantipsychotics,clozapinehasanincreasedriskofblooddyscrasias,inparticularagranulocytosis,inthefirst18weeksoftreatment.Afteroneyear,thisriskreducestothatassociatedwithmostantipsychotics.Clozapine'suseisthereforereservedforpeoplewhohavenotrespondedtotwootherantipsychoticsandisonlydonewithstringentbloodmonitoring.[5]Overall,despitetheconcernsrelatingtobloodandothersideeffects,clozapineuseisassociatedwithareducedmortality,especiallyfromsuicidewhichisamajorcauseofprematuredeathinpeoplewithschizophrenia.[21]Theriskofclozapinerelatedagranulocytosisandneutropeniawarrantedthemandatoryuseofstringentriskmonitoringandmanagementsystems,whichhavereducedtheriskofdeathfromtheseadverseeventstoaround1in7,700.[22]Theassociationbetweenclozapineuseandspecificbloodsdyscrasiaswasfirstnotedinthe1970swheneightdeathsfromagranulocytosiswerenotedinFinland.[23]Atthetimeitwasnotclearifthisexceededtheestablishedrateofthissideeffectwhichisalsofoundinotherantipsychoticsandalthoughthedrugwasnotcompletelywithdrawn,itsusebecamelimited.[24]Clozapinebecamewidelyavailableintheearly1990sandremainstheonlytreatmentlikelytobeeffectiveintreatingresistantschizophrenia. Commonadverseeffectsincludedrowsiness,constipation,hypersalivation(increasedsalivaproduction),tachycardia,lowbloodpressure,blurredvision,weightgain,anddizziness.[25]Clozapineisnotnormallyassociatedwithtardivedyskinesia(TD)andisrecommendedasthedrugofchoicewhenthisispresent,althoughsomecasereportsdescribeclozapine-inducedTD.[26]Otherseriousrisksincludeseizures,inflammationoftheheart,highbloodsugarlevels,constipation.Theuseofthisdrugcanrarelyresultinclozapine-inducedgastrichypomotilitysyndromewhichmayleadtobowelobstructionanddeath,andinolderpeoplewithpsychosis,asaresultofdementiaitmayleadtoanincreasedriskofdeath.[27][28]Themechanismofactionisnotentirelyclearinthecurrentmedicalliterature.[25]ClozapineisontheWorldHealthOrganization'sListofEssentialMedicineswhichliststhesafestandmosteffectivemedicinesneededinahealthsystem.[29]Itisavailableasagenericmedication.[25] Contents 1History 2Chemistry 3Clinicaluses 3.1Schizophrenia 3.2Bipolardisorder 3.3Severepersonalitydisorders 3.4Initiation 3.5Monitoring 3.6ClozapineResponseandTreatmentOptimisation 3.6.1Optimisingbloodsampling 3.6.2UnderuseofClozapine 3.6.2.1Racialdisparityintheuseofclozapine 3.6.2.2Benignethnicneutropenia 4Adverseeffects 4.1Neutropeniaandagranulocytosis 4.1.1Clozapinerechallenge 4.2Cardiactoxicity 4.3Gastrointestinalhypomotility 4.4Hypersalivation 4.5Centralnervoussystem 4.6Urinaryincontinence 4.7Withdrawaleffects 4.8Weightgainanddiabetes 4.9Pneumonia 4.10Overdose 5Druginteractions 6Pharmacology 6.1Pharmacodynamics 6.2Pharmacokinetics 7Societyandculture 7.1Economics 7.2Clozapineinthearts 8References 9Furtherreading 10Externallinks History[edit] Clozapinewassynthesizedin1956[15]byWanderAG,aSwisspharmaceuticalcompany,basedonthechemicalstructureofthetricyclicantidepressantimipramine.Thefirsttestinhumansin1962wasconsideredafailure.TrialsinGermanyin1965and1966aswellasatrialinViennain1966weresuccessful.In1967WanderAGwasacquiredbySandoz.[24]Furthertrialstookplacein1972whenclozapinewasreleasedinSwitzerlandandAustriaasLeponex.TwoyearslateritwasreleasedinWestGermanyandFinlandin1975.EarlytestingwasperformedintheUnitedStatesaroundthesametime.[24]In197516casesofagranulocytosisleadingto8deathsinclozapine-treatedpatientswerereportedfrom6hospitals,mostlyinsouthwesternFinlandledtoconcern.[30]AnalysisoftheFinnishcasesrevealedthatalltheagranulocytosiscaseshadoccurredwithinthefirst18weeksoftreatmentandtheauthorsproposedbloodmonitoringduringthisperiod.[31]TherateofagranulocytosisinFinlandappearedtobe20timeshigherthanintherestoftheworldandtherewasspeculationthatthismayhavebeendueauniquegeneticdiversityintheregion.[23][32][33]WhilstthedrugcontinuedtobemanufacturedbySandozandremainedavailableinEuropedevelopmentintheU.S.halted. InterestinclozapinecontinuedinaninvestigationalcapacityintheUnitedStatesbecause,eveninthe1980s,thedurationofhospitalisation,especiallyinStateHospitalsforthosewithtreatmentresistantschizophreniamightoftenbemeasuredinyearsratherthandays.[24]TheroleofclozapineintreatmentresistantschizophreniawasestablishedbythelandmarkClozarilCollaborativeStudyGroupStudy#30inwhichclozapineshowedmarkedbenefitscomparedtochlorpromazineinagroupofpatientswithprotractedpsychosisandwhohadalreadyshownaninadequateresponsetootherantipsychotics.Thisinvolvedbothstringentbloodmonitoringandadouble-blinddesignwiththepowertodemonstratesuperiorityoverstandardantipsychotictreatment.Theinclusioncriteriawerepatientswhohadfailedtorespondtoatleastthreepreviousantipsychoticsandhadthennotrespondedtoasingleblindtreatmentwithhaloperidol(meandose61 mg+/-14 mg/d).Twohundredandsixty-eightwererandomisedweretodoubleblindtrialsofclozapine(upto900 mg/d)orchlorpromazine(upto1800 mg/d).30%oftheclozapinepatientsrespondedcomparedto4%ofthecontrols,withsignificantlygreaterimprovementontheBriefPsychiatricRatingScale,ClinicalGlobalImpressionScale,andNurses'ObservationScaleforInpatientEvaluation;thisimprovementincluded"negative"aswellaspositivesymptomareas.[15]Followingthisstudy,theUSFoodandDrugAdministration(FDA)approveditsusein1990.Cautiousofthisrisk,however,theFDArequiredablackboxwarningforspecificsideeffectsincludingagranulocytosis,andtooktheuniquestepofrequiringpatientstoberegisteredinaformalsystemoftrackingsothatbloodcountlevelscouldbeevaluatedonasystematicbasis.[33][34] InDecember2002,clozapinewasapprovedintheUSforreducingtheriskofsuicideinpeoplewithschizophreniaorschizoaffectivejudgedtobeatchronicriskforsuicidalbehavior.[35]In2005,theFDAapprovedcriteriatoallowreducedbloodmonitoringfrequency.[36]In2015,theindividualmanufacturerPatientRegistrieswereconsolidatedbyrequestoftheFDAintoasinglesharedPatientRegistryCalledTheClozapineREMSRegistry.[37]DespitethedemonstratedsafetyofthenewFDAmonitoringrequirements,whichhavelowerneutrophillevelsanddonotincludetotalwhitecellcounts,internationalmonitoringhasnotbeenstandardised.[38][39][40] Chemistry[edit] Clozapineisadibenzodiazepinethatisstructurallyrelatedtoloxapine.Itisslightlysolubleinwater,solubleinacetone,andhighlysolubleinchloroform.Itssolubilityinwateris0.1889 mg/L(25 °C).[3]Itsmanufacturer,Novartis,claimsasolubilityof<0.01%inwater(<100 mg/L).[41] Clinicaluses[edit] Schizophrenia[edit] Clozapineisusuallyusedforpeoplediagnosedwithschizophreniawhohavehadaninadequateresponsetootherantipsychoticsorwhohavebeenunabletotolerateotherdrugsduetoextrapyramidalsideeffects.ItisalsousedforthetreatmentofpsychosisinParkinson'sDisease.[5][6]Itisregardedasthegold-standardtreatmentwhenothermedicationhasbeeninsufficientlyeffectiveanditsuseisrecommendedbymultipleinternationaltreatmentguidelines,supportedbysystematicreviewsandmeta-analysis.[7][8][9][10][11][12][42][43]Whilstallcurrentguidelinesreserveclozapinetoindividualswhentwootherantipsychoticsevidenceindicatesthatclozapinemightbeusedasasecondlinedrug.[44]Clozapinetreatmenthasbeendemonstratedtoproducedimprovedoutcomesinmultipledomainsincluding;areducedriskofhospitalisation,areducedriskofdrugdiscontinuation,areductioninoverallsymptomsandhasimprovedefficacyinthetreatmentofpositivepsychoticsymptomsofschizophrenia.[17][45][46]Despitearangeofsideeffectspatientsreportgoodlevelsofsatisfactionandlongtermadherenceisfavourablecomparedtootherantipsychotics.[47]Verylongtermfollow-upstudiesrevealmultiplebenefitsintermsofreducedmortality,[16][48]withaparticularlystrongeffectforreduceddeathbysuicide,clozapineistheonlyantipsychoticknowntohaveaneffectreducingtheriskofsuicideorattemptedsuicide.[49]Clozapinehasasignificantanti-aggressiveeffect.[50][51][52][53][54]Clozapineiswidelyusedinsecureandforensicmentalhealthsettingswhereimprovementsinaggression,shortenedadmissionandreductionsinrestrictivepracticesuchasseclusionhavebeenfound.[55][56][57][58][59][60][61][62][63]Insecurehospitalsandothersettingsclozapinehasalsobeenusedinthetreatmentofborderlineandantisocialpersonalitydisorderwhenthishasbeenassociatedwithviolenceorself-harm.[64][65][50]Althoughoraltreatmentisalmostuniversalclozapinehasonoccasionbeenenforcedusingeithernasogastricorashortactinginjectionalthoughinalmost50%oftheapproximately100reportedcasespatientsagreedtotakeoralmedicationpriortotheuseofacoerciveintervention.[56][66][58][67][68][69][70][60][71][59][72] Bipolardisorder[edit] Onthebasisofsystematicreviewsclozapineisrecommendedinsometreatmentguidelinesasathirdorfourthlinetreatmentforrefractorybipolardisorder.[73][74][75][76]Bipolardisorderisanunlicensedindicationforclozapine.[citationneeded] Severepersonalitydisorders[edit] Clozapineisalsousedinemotionallyunstablepersonalitydisorderandarandomisedcontrolledtrialiscurrentlyunderway.[77][78][79][80][65][81][82][64][83]Theuseofclozapinetotreatpersonalitydisorderisuncommonandunlicensed. Initiation[edit] Whilstclozapineisusuallyinitiatedinhospitalsettingcommunityinitiationisalsoavailable.[84][85]Beforeclozapinecanbeinitiatedmultipleassessmentsandbaselineinvestigationsareperformed.IntheUKandIrelandtheremustbeanassessmentthatthepatientsatisfiesthecriteriaforprescription;treatmentresistantschizophrenia,intoleranceduetoextrapyramidalsymptomsofotherantipsychoticsorpsychosisinparkinson'sdisease.Establishingahistoryoftreatmentresistancemayincludecarefulreviewofthemedicationhistoryincludingthedurations,dosesandcomplianceofpreviousantipsychotictherapyandthatthesedidnothaveanadequateclinicaleffect.Adiagnosticreviewmayalsobeperformed.Thatcouldincludereviewofantipsychoticplasmaconcentrationsifavailable.Theprescriber,patient,pharmacyandthelaboratoryperformingbloodcountsareallregisteredwithaspecifiedclozapineproviderwhomustbeadvisedthatthereisnohistoryofneutropeniafromanycause.Theclozapineproviderscollaboratebysharinginformationregardingpatientswhohavehadclozapinerelatedneutropeniaoragranulocytosissothatclozapinecannotbeusedagainonlicense.Clozapinemayonlybedispensedafterasatisfactorybloodresulthasbeenreceivedbytheriskmonitoringagencyatwhichpointanindividualprescriptionmaybereleasedtoanindividualpatientonly.[86] Baselinetestsusuallyalsoinclude;aphysicalexaminationincludingbaselineweight,waistcircumferenceandBMI,assessmentsofrenalfunctionandliverfunction,anECGandotherbaselinebloodsmayalsobetakentofacilitatemonitoringofpossiblemyocarditis,thesemightincludeCreactiveprotein(CRP)andtroponin.InAustraliaandNewZealandpre-clozapineechocardiogramsarealsocommonlyperformed.[87]Anumberofserviceprotocolsareavailableandtherearevariationsintheextentofpreclozapineworkups.Somemightalsoincludefastinglipids,HbA1candprolactin.AttheMaudsleyHospitalintheUKtheTreatservicealsoroutinelyperformsawidevarietyofotherinvestigationsincludingmultipleinvestigationsforothercausesofpsychosisandcomorbiditiesincluding;MRIbrainimaging,thyroidfunctiontests,B12,folateandserumcalciumlevels,infectionscreeningforbloodbornevirusesincludingHepatitisBandC,HIVandsyphilisaswellasscreeningforautoimmunepsychosisbyanti-NMDA,anti-VGKCandAnti-nuclearAntibodyscreening.Investigationsusedtomonitorthepossibilityofclozapinerelatedsideeffectssuchasmyocarditisarealoperformedincludingbaselinetroponin,CRPandBNPandforneurolepticmalignantsyndromeCK.[85] Thedoseofclozapineisinitiallylowandgraduallyincreasedoveranumberofweeks.Initialdosesmayrangefrom6.5-12.5 mg/dincreasingstepwisetypicallytodosesintherangeof250–350 mgperdayatwhichpointanassessmentofresponsewillbeperformed.[87]IntheUKtheaverageclozapinedoseis450 mg/d.[88][89]Butresponseishighlyvariableandsomepatientsrespondatmuchlowerdosesandviceversa. Monitoring[edit] Duringtheinitialdosetitrationphasethefollowingaretypicallymonitored;usuallydailyatfirst;pulse,bloodpressureandsinceorthostatichypotensioncanbeproblematicthisshouldbemonitoredbothsittingandstanding.Ifthereisasignificantdropthentherateofthedoseincreasemaybeslowed,temperature.[85] Weeklytestsinclude;Mandatoryfullbloodcountsareperformedweeklyforthefirst18weeks.Insomeservicestherewillalsobemonitoringofmarkersthatmightindicatemyocarditis;troponin,CRPandBNPalthoughtheexacttestsandfrequencyvarybetweenservices.Weightisusuallymeasuredweekly. Thereonotherinvestigationsandmonitoringwillalwaysincludefullbloodcounts(fortnightlyfor1yearthenmonthly).Weight,waistcircumference,lipidsandglucoseorHbA1cmayalsobemonitored. ClozapineResponseandTreatmentOptimisation[edit] Aswithotherantipsychotics,andincontrasttoreceivedwisdom,responsestoclozapinearetypicallyseensoonafterinitiationandoftenwithinthefirstweek.[90][91]Thatsaidresponses,especiallythosewhicharepartial,canbedelayed.[92]Quitewhatanadequatetrialofclozapineis,isuncertainbutarecommendationisthatthisshouldbeforatleast8weeksonaplasmatroughlevelabove350-400microg/L.[93][94]Thereisconsiderableinter-individualvariation.Asignificantnumberofpatientsrespondatlowerandalsomuchhigherplasmaconcentrationsandsomepatients,especiallyyoungmalesmokersmayneverachievetheseplasmalevelsevenatdosesof900 mg/day.Optionsthenincludeeitherincreasingthedoseabovethelicensedmaximumortheadditionofadrugthatinhibitsclozapinemetabolism.Avoidingunnecessarypolypharmacyisageneralprincipleindrugtreatment. Optimisingbloodsampling[edit] Theneutrophilcutoffforclozapinehaveshownanexceptionalabilitytomitigatetheriskofneutropeniaandagranulocytosis.Thereisasignificantmarginofsafety.Somepatientsmayhavemarginalneutrophilcountsbeforeandafterinitiationandtheyareatriskofprematureclozapinediscontinuation.Aknowledgeofneutrophilbiologyallowsbloodsamplingoptimisation.NeutrophilsshowadiurnalvariationinresponsetothenaturalcycleofG-CSFproduction,theyareincreasedintheafternoons,theyarealsomobilisedintothecirculationafterexerciseandsmoking.Simplyshiftingbloodsamplinghasbeenshowntoavoidunnecessarydiscontinuations,especiallyinblackpopulations.Howeverthisisadisruptiontousualhospitalpractice.Otherpracticalstepsaretoensurethatbloodresultsbecomeavailableinhoursandwhenseniorstaffareavailable.[95] UnderuseofClozapine[edit] Clozapineiswidelyrecognisedasbeingunderusedwithwidevariationinprescribing,[96][97][98][99][100][101][102][103]especiallyinpatientswithAfricanheritage.[104][105][106][107][108] Psychiatristsprescribingpracticeshavebeenfoundtobethemostsignificantvariableregardingvarianceinitsuse.[citationneeded]Surveysofpsychiatristsattitudestoclozapinehavefoundthatmanyhadlittleexperienceinitsuse,overestimatedtheincidenceandwerefearfulofsideeffects,anddidnotappreciatethatmanypatientsprefertotakeclozapinethanotherantipsychoticsarereluctanttoprescribeclozapine,hadlittleexperienceinitsuseandbelievedthatpatientstreatedwithclozapinewerelesssatisfiedthanthosetreatedwithotherantipsychotics.[109][110][111]Incontrasttomanypsychiatristsexpectationsmostpatientsbelievethatthebloodtestingandotherdifficultiesareworththemultiplebenefitsthattheyperceive.[112][20]Whilstpsychiatristsfearthesevereadverseeffectssuchasagranulocytosis,patientsaremoreconcernedabouthypersalivation.[113]Clozapineisnolongeractivelymarketedandthismayalsobeoneoftheexplanationsforitsunderuse.[114] Despitethestrongevidenceanduniversalendorsementbynationalandinternationaltreatmentguidelinesandtheexperiencesofpatientsthemselves,mostpeopleeligibleforclozapinearenottreatedwithit.[19]AlargestudyinEnglandfoundthatapproximately30%ofthoseeligibleforclozapinewerebeingtreatedwithit.[115]Thosepatientsthatdostartclozapineusuallyfaceprolongeddelay,multipleepisodesofpsychosisandtreatmentssuchashighdoseantipsychoticsorpolypharmacy.Insteadoftwopreviousantipsychoticsmanywillhavebeenexposedtotenormoredrugswhichwerenoteffective.Inastudyof120patientsconductedinfourhospitalsinSouth-EastLondon,foundameanof9.2episodesofantipsychoticprescriptionbeforeclozapinewasinitiatedandthemeandelayinusingclozapinewas5years.[116]Treatmentsthathavenoevidencebaseorareregardedasactivelyharmfulareusedinsteadmultipleandorhigh-dosetreatment.[117] Racialdisparityintheuseofclozapine[edit] Ageneralfindinginhealthcareprovisionisthatminoritygroupsreceiveinferiortreatment,thisisaparticularfindingintheUS.[118][119][120][121]IntheUSageneralfindingisthatcomparedtotheirwhitepeersAfricanAmericanpeoplearelesslikelytobeprescribedthesecondgenerationantipsychotics,whicharemoreexpensivethanalternativesandthiswasevenapparentandespeciallysoforclozapinewhencomparisonwasmadeintheVeteransAffairsmedicalsystemandwhendifferencesregardingsocioeconomicfactorsweretakenintoaccount.[122][123][124]Aswellasbeinglesslikelytostartclozapineblackpatientsaremorelikelytostopclozapine,possiblyonaccountofbenignethnicneutropenia. Benignethnicneutropenia[edit] Benignreductionsinneutrophilsareobservedinindividualsofallethnicbackgroundsethnicneutropenia(BEN),neutropeniawithoutimmunedysfunctionorincreasedliabilitytoinfectionisnotduetoabnormalneutrophilproduction;although,theexactaetiologyofthereductionincirculatingcellsremainsunknown.BENisassociatedwithseveralethnicgroups,butinparticularthosewithBlackAfricanandWestAfricanancestry.[125]Adifficultywiththeuseofclozapineisthatneutrophilcountshavebeenstandardisedonwhitepopulations.[126]ForsignificantnumbersofblackpatientsthestandardneutrophilcountthresholdsdidnotpermitclozapineuseasthethresholdsdidnottakeBENintoaccount.Since2002,clozapinemonitoringservicesintheUKhaveusedreferenceranges0.5 × 109/llowerforpatientswithhaematologicallyconfirmedBENandsimilaradjustmentsareavailableinthecurrentUScriteria,althoughwithlowerpermissibleminima.[62][39][127]Buteventhensignificantnumbersofblackpatientswillnotbeeligibleeventhoughthelowneutrophilcountsdonotintheircasereflectdisease.TheDuffy–Nullpolymorphism,whichprotectsagainstsometypesofmalaria,ispredictiveofBEN.[128] Adverseeffects[edit] Clozapinemaycauseseriousandpotentiallyfataladverseeffects.Clozapinecarriesfiveblackboxwarnings,including(1)severeneutropenia(lowlevelsofneutrophils),(2)orthostatichypotension(lowbloodpressureuponchangingpositions),includingslowheartrateandfainting,(3)seizures,(4)myocarditis(inflammationoftheheart),and(5)riskofdeathwhenusedinelderlypeoplewithdementia-relatedpsychosis.[2]Loweringoftheseizurethresholdmaybedoserelated.Increasingthedoseslowlymaydecreasetheriskforseizuresandorthostatichypotension.[129] Commoneffectsincludeconstipation,bed-wetting,night-timedrooling,musclestiffness,sedation,tremors,orthostatichypotension,highbloodsugar,andweightgain.Theriskofdevelopingextrapyramidalsymptoms,suchastardivedyskinesia,isbelowthatoftypicalantipsychotics;thismaybeduetoclozapine'santicholinergiceffects.Extrapyramidalsymptomsmaysubsidesomewhatafterapersonswitchesfromanotherantipsychotictoclozapine.[129]Sexualproblems,likeretrogradeejaculation,havebeenreportedwhiletakingclozapine.[2]Despitethehighriskfornumerousseveresideeffects,somemedicalprofessionalsinsistthatmostsideeffectscanbemanagedwhilecontinuingtotakeclozapine.[130] Neutropeniaandagranulocytosis[edit] Mainarticle:Agranulocytosis ClozapineInducedNeutropenia(CIN)occursinapproximately3.8%ofcasesandClozapineInducedAgranulocytosis(CIA)in0.4%.[131]Thesearepotentiallyserioussideeffectsandagranulocytosiscanresultindeath.Tomitigatethisriskclozapineisonlyusedwithmandatoryabsoluteneutrophilcount(ANC)monitoring(neutrophilsarethemostabundantofthegranulocytes);forexample,intheUnitedStates,theRiskEvaluationandMitigationStrategy(REMS).[132]Theexactschedulesandbloodcountthresholdsvaryinternationally[39]andthethresholdsatwhichclozapinecanbeusedintheU.S.hasbeenlowerthanthosecurrentlyusedintheU.K.andAustraliasiaforsometime.[133]Theeffectivenessoftheriskmanagementstrategiesusedissuchthatdeathsfromthesesideeffectsareveryrareoccurringatapproximately1in7700patientstreated.[22]Almostalltheadversebloodreactionsoccurwithinthefirstyearoftreatmentandthemajoritywithinthefirst18weeks.[131]Afteroneyearoftreatmenttheserisksreducemarkedlytothatseeninotherantipsychoticdrugs0.01%orabout1in10,000andtheriskofdeathismarkedlylowerstill.[22]Whenreductionsinneutrophillevelsarenotedonregularbloodmonitoringthen,dependingonthevalue,monitoringmaybeincreasedor,iftheneutrophilcountissufficientlylow,thenclozapineisstoppedimmediatelyandcanthennolongerbeusedwithinthemedicinallicence.Stoppingclozapinealmostalwaysresultsinresolutionoftheneutrophilreduction.[131][22]Howeversevereagranulocytosiscanresultinspontaneousinfectionanddeath.isaseveredecreaseintheamountofaspecifickindofwhitebloodcellcalledgranulocytes.Clozapinecarriesablackboxwarningfordrug-inducedagranulocytosis.Rapidpoint-of-caretestsmaysimplifythemonitoringforagranulocytosis.[134] Clozapinerechallenge[edit] Aclozapine"rechallenge"iswhensomeonethatexperiencedagranulocytosiswhiletakingclozapinestartstakingthemedicationagain.IncountriesinwhichtheneutrophilthresholdsarehigherthanthoseusedintheUSasimpleapproachis,ifthelowestANChadbeenabovetheUScutoff,toreintroduceclozapinebutwiththeUSmonitoringregime.ThishasbeendemonstratedinalargecohortofpatientsinahospitalinLondoninwhichitwasfoundthatof115patientswhohadhadclozapinestoppedaccordingtotheUScriteriaonly7wouldhavehadclozapinestoppediftheUScutoffshadbeenused.Ofthese62wererechallenged,59continuedtouseclozapinewithoutdifficultyandonly1hadafallinneutrophilsbelowtheUScutoff.[135]Otherapproacheshaveincludedtheuseofotherdrugstosupportneutrophilcountsincludinglithiumorgranulocytecolony-stimulatingfactor(G-CSF).However,ifagranulocytosisstilloccursduringarechallenge,thealternativeoptionsarelimited.[136][137] Cardiactoxicity[edit] Clozapinecanrarelycausemyocarditisandcardiomyopathy.Alargemeta-analysisofclozapineexposuretoover250,000peoplerevealedthattheseoccurredinapproximately7in1000patientstreatedandresultedindeathin3and4in10,000patientsexposedrespectivelyandmyocarditisoccurredalmostexclusivelywithinthefirst8weeksoftreatment,cardiomyopathycanoccurmuchlateron.[138]Firstmanifestationsofillnessarefeverwhichmaybeaccompaniedbysymptomsassociatedwithupperrespiratorytract,gastrointestinalorurinarytractinfection.TypicallyC-reactiveprotein(CRP)increaseswiththeonsetoffeverandrisesinthecardiacenzyme,troponin,occurupto5dayslater.MonitoringguidelinesadvisecheckingCRPandtroponinatbaselineandweeklyforthefirst4weeksafterclozapineinitiationandobservingthepatientforsignsandsymptomsofillness.[139]Signsofheartfailurearelesscommonandmaydevelopwiththeriseintroponin.Arecentcase-controlstudyfoundthattheriskofclozapine-inducedmyocarditisisincreasedwithincreasingrateofclozapinedosetitration,increasingageandconcomitantsodiumvalproate.[140]Alargeelectronichealthregisterstudyhasrevealedthatnearly90%ofcasesofsuspectedclozapinerelatedmyocarditisarefalsepositives.[141]Rechallengeafterclozapineinducedmyocarditishasbeenperformedandaprotocolforthisspecialistapproachhasbeenpublished.[142]Asystematicreviewofrechallengeaftermyocarditishasshowsuccessinover60%ofreportedcases.[143] Gastrointestinalhypomotility[edit] Anotherunderrecognizedandpotentiallylife-threateningeffectspectrumisgastrointestinalhypomotility,whichmaymanifestassevereconstipation,fecalimpaction,paralyticileus,bowelobstruction,acutemegacolon,ischemiaornecrosis.[144]Colonichypomotilityhasbeenshowntooccurinupto80%ofpeopleprescribedclozapinewhengastrointestinalfunctionismeasuredobjectivelyusingradiopaquemarkers.[145]Clozapine-inducedgastrointestinalhypomotilitycurrentlyhasahighermortalityratethanthebetterknownsideeffectofagranulocytosis.[146]ACochranereviewfoundlittleevidencetohelpguidedecisionsaboutthebesttreatmentforgastrointestinalhypomotilitycausedbyclozapineandotherantipsychoticmedication.[147]Monitoringbowelfunctionandthepreemptiveuseoflaxativesforallclozapine-treatedpeoplehasbeenshowntoimprovecolonictransittimesandreduceserioussequelae.[148] Hypersalivation[edit] Hypersalivation,ortheexcessiveproductionofsaliva,isoneofthemostcommonadverseeffectsofclozapine(30-80%).[149]Thesalivaproductionisespeciallybothersomeatnightandfirstthinginthemorning,astheimmobilityofsleepprecludesthenormalclearanceofsalivabyswallowingthatoccursthroughouttheday.[149]WhileclozapineisamuscarinicantagonistattheM1,M2,M3,andM5receptors,clozapineisafullagonistattheM4subset.BecauseM4ishighlyexpressedinthesalivarygland,itsM4agonistactivityisthoughttoberesponsibleforhypersalivation.[150]Clozapine-inducedhypersalivationislikelyadose-relatedphenomenon,andtendstobeworsewhenfirststartingthemedication.[149]Besidesdecreasingthedoseorslowingtheinitialdosetitration,otherinterventionsthathaveshownsomebenefitincludesystemically-absorbedanticholinergicmedicationssuchashyoscine,[151]diphenhydramine[149]andtopicalanticholinergicmedicationslikeipratropiumbromide.[152]Mildhypersalivationmaybemanagedbysleepingwithatoweloverthepillowatnight.[152] Centralnervoussystem[edit] CNSsideeffectsincludedrowsiness,vertigo,headache,tremor,syncope,sleepdisturbances,nightmares,restlessness,akinesia,agitation,seizures,rigidity,akathisia,confusion,fatigue,insomnia,hyperkinesia,weakness,lethargy,ataxia,slurredspeech,depression,myoclonicjerks,andanxiety.Rarelyseenaredelusions,hallucinations,delirium,amnesia,libidoincreaseordecrease,paranoiaandirritability,abnormalEEG,worseningofpsychosis,paresthesia,statusepilepticus,andobsessivecompulsivesymptoms.Similartootherantipsychoticsclozapinerarelyhasbeenknowntocauseneurolepticmalignantsyndrome.[153] Urinaryincontinence[edit] Clozapineislinkedtourinaryincontinence,[154]thoughitsappearancemaybeunder-recognized.[155] Withdrawaleffects[edit] Abruptwithdrawalmayleadtocholinergicreboundeffects,suchasindigestion,diarrhea,nausea/vomiting,overabundanceofsaliva,profusesweating,insomnia,andagitation.[156]Abruptwithdrawalcanalsocauseseveremovementdisorders,catatonia,andpsychosis.[157]Doctorshaverecommendedthatpatients,families,andcaregiversbemadeawareofthesymptomsandrisksofabruptwithdrawalofclozapine.Whendiscontinuingclozapine,gradualdosereductionisrecommendedtoreducetheintensityofwithdrawaleffects.[158][159] Weightgainanddiabetes[edit] Inadditiontohyperglycemia,significantweightgainisfrequentlyexperiencedbypatientstreatedwithclozapine.[160]Impairedglucosemetabolismandobesityhavebeenshowntobeconstituentsofthemetabolicsyndromeandmayincreasetheriskofcardiovasculardisease.Thedatasuggestthatclozapinemaybemorelikelytocauseadversemetaboliceffectsthansomeoftheotheratypicalantipsychotics.[161] Pneumonia[edit] Internationaladversedrugeffectdatabasesindicatethatclozapineuseisassociatedwithasignificantlyincreasedincidenceofanddeathfrompneumoniaandthismaybeoneofthemostsignificantadverseevents.[162]Themechanismsforthisareunknownalthoughithasbeenspeculatedthatitmayberelatedtohypersalivation,immuneeffectsofclozapine'seffectsontheresolutionofinflammation.[163][164] Overdose[edit] Thissectionneedsexpansion.Youcanhelpbyaddingtoit.(August2019) Symptomsofoverdosecaninclude;sedation,confusion,tachycardia,seizuresandataxia.Fatalitieshavebeenreportedduetoclozapineoverdose,thoughoverdoses>4000 mghavebeensurvived.[165] Druginteractions[edit] Fluvoxamineinhibitsthemetabolismofclozapineleadingtosignificantlyincreasedbloodlevelsofclozapine.[166] Whencarbamazepineisconcurrentlyusedwithclozapine,ithasbeenshowntodecreaseplasmalevelsofclozapinesignificantlytherebydecreasingthebeneficialeffectsofclozapine.[167][168]Patientsshouldbemonitoredfor"decreasedtherapeuticeffectsofclozapineifcarbamazepine"isstartedorincreased.Ifcarbamazepineisdiscontinuedorthedoseofcarbamazepineisdecreased,therapeuticeffectsofclozapineshouldbemonitored.Thestudyrecommendscarbamazepinetonotbeusedconcurrentlywithclozapineduetoincreasedriskofagranulocytosis.[169] CiprofloxacinisaninhibitorofCYP1A2andclozapineisamajorCYP1A2substrate.Randomizedstudyreportedelevationinclozapineconcentrationinsubjectsconcurrentlytakingciprofloxacin.[170]Thus,theprescribinginformationforclozapinerecommends"reducingthedoseofclozapinebyone-thirdoforiginaldose"whenciprofloxacinandotherCYP1A2inhibitorsareaddedtotherapy,butonceciprofloxacinisremovedfromtherapy,itisrecommendedtoreturnclozapinetooriginaldose.[171] Pharmacology[edit] Pharmacodynamics[edit] Seealso:Atypicalantipsychotic§ Pharmacodynamics,andAntipsychotic§ Comparisonofmedications Clozapineandnorclozapinebinding[172][173] Protein CZPKi(nM) NDMCKi(nM) 5-HT1A 123.7 13.9 5-HT1B 519 406.8 5-HT1D 1,356 476.2 5-HT2A 5.35 10.9 5-HT2B 8.37 2.8 5-HT2C 9.44 11.9 5-HT3 241 272.2 5-HT5A 3,857 350.6 5-HT6 13.49 11.6 5-HT7 17.95 60.1 α1A 1.62 104.8 α1B 7 85.2 α2A 37 137.6 α2B 26.5 95.1 α2C 6 117.7 β1 5,000 6,239 β2 1,650 4,725 D1 266.25 14.3 D2 157 101.4 D3 269.08 193.5 D4 26.36 63.94 D5 255.33 283.6 H1 1.13 3.4 H2 153 345.1 H3 >10,000 >10,000 H4 665 1,028 M1 6.17 67.6 M2 36.67 414.5 M3 19.25 95.7 M4 15.33 169.9 M5 15.5 35.4 SERT 1,624 316.6 NET 3,168 493.9 DAT >10,000 >10,000 Thesmallerthevalue,themorestronglythedrugbindstothesite.Alldataareforclonedhumanproteins.[172][173] Clozapineisclassifiedasanatypicalantipsychoticdrugbecauseitbindstoserotoninaswellasdopaminereceptors.[174] Clozapineisanantagonistatthe5-HT2Asubunitoftheserotoninreceptor,putativelyimprovingdepression,anxiety,andthenegativecognitivesymptomsassociatedwithschizophrenia.[175][176] AdirectinteractionofclozapinewiththeGABABreceptorhasalsobeenshown.[177]GABABreceptor-deficientmiceexhibitincreasedextracellulardopaminelevelsandalteredlocomotorbehaviourequivalenttothatinschizophreniaanimalmodels.[178]GABABreceptoragonistsandpositiveallostericmodulatorsreducethelocomotorchangesinthesemodels.[179] ClozapineinducesthereleaseofglutamateandD-serine,anagonistattheglycinesiteoftheNMDAreceptor,fromastrocytes,[180]andreducestheexpressionofastrocyticglutamatetransporters.Thesearedirecteffectsthatarealsopresentinastrocytecellculturesnotcontainingneurons.ClozapinepreventsimpairedNMDAreceptorexpressioncausedbyNMDAreceptorantagonists.[181] Pharmacokinetics[edit] N-desmethylclozapine(norclozapine),clozapine'smajoractivemetabolite. Theabsorptionofclozapineisalmostcompletefollowingoraladministration,buttheoralbioavailabilityisonly60to70%duetofirst-passmetabolism.Thetimetopeakconcentrationafteroraldosingisabout2.5hours,andfooddoesnotappeartoaffectthebioavailabilityofclozapine.However,itwasshownthatco-administrationoffooddecreasestherateofabsorption.[182]Theeliminationhalf-lifeofclozapineisabout14hoursatsteadystateconditions(varyingwithdailydose).[medicalcitationneeded] Clozapineisextensivelymetabolizedintheliver,viathecytochromeP450system,topolarmetabolitessuitableforeliminationintheurineandfeces.Themajormetabolite,norclozapine(desmethyl-clozapine),ispharmacologicallyactive.ThecytochromeP450isoenzyme1A2isprimarilyresponsibleforclozapinemetabolism,but2C,2D6,2E1and3A3/4appeartoplayrolesaswell.Agentsthatinduce(e.g.,cigarettesmoke)orinhibit(e.g.,theophylline,ciprofloxacin,fluvoxamine)CYP1A2mayincreaseordecrease,respectively,themetabolismofclozapine.Forexample,theinductionofmetabolismcausedbysmokingmeansthatsmokersrequireuptodoublethedoseofclozapinecomparedwithnon-smokerstoachieveanequivalentplasmaconcentration.[183] Clozapineandnorclozapine(desmethyl-clozapine)plasmalevelsmayalsobemonitored,thoughtheyshowasignificantdegreeofvariationandarehigherinwomenandincreasewithage.[184]Monitoringofplasmalevelsofclozapineandnorclozapinehasbeenshowntobeusefulinassessmentofcompliance,metabolicstatus,preventionoftoxicity,andindoseoptimisation.[183] Societyandculture[edit] Listoftradenamesforclozapine[1] A Alemoxan,Azaleptine,Azaleptol C Cloment,Clonex,Clopin,Clopine,Clopsine,Cloril,Clorilex,Clozamed,Clozapex,Clozapin,Clozapina,Clozapinum,Clozapyl,Clozarem,Clozaril D Denzapine,Dicomex E Elcrit,Excloza F FazaClo,Froidir I Ihope K Klozapol L Lanolept,Lapenax,Leponex,Lodux,Lozapine,Lozatric,Luften M Medazepine,Mezapin N Nemea,Nirva O Ozadep,Ozapim R Refract,Refraxol S Sanosen,Schizonex,Sensipin,Sequax,Sicozapina,Sizoril,Syclop,Syzopin T Tanyl U Uspen V Versacloz X Xenopal Z Zaclo,Zapenia,Zapine,Zaponex,Zaporil,Ziproc,Zopin Economics[edit] Despitetheexpenseoftheriskmonitoringandmanagementsystemsrequired,clozapineuseishighlycosteffective;withanumberofstudiessuggestingsavingsoftensofthousandsofdollarsperpatientperyearcomparedtootherantipsychoticsaswellasadvantagesregardingimprovementsinqualityoflife.[185][186][187]Clozapineisavailableasagenericmedication.[25] Clozapineinthearts[edit] CarrieMathison,afictionalCIAoperativeinthetelevisionseriesHomelandsecretlytakesclozapinesuppliedbyhersisterforthetreatmentofbipolaraffectivedisorder. InthefilmOutofDarknessDianaRossplayedtheprotagonistPaulieCooper,'aparanoidschizophrenic'whoisdepictedashavingadramaticimprovementonclozapine. DHA-clozapine InthetelevisionseriesLastManOnEarth(2015)thecharacterMelissahasapsychoticepisodeandreturnshomeandstartsactinghowshedidpre-pandemic.HerboyfriendToddseeshertakeamedicationinthemorningandasksherwhatitis.Allshewillsayis"SantasPenis".Toddsearchesmedicationbooksandfindsclozapine=Clauseapeen. 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Furtherreading[edit] author.,Stahl,StephenM.,1951-(16May2019).Theclozapinehandbook.ISBN 978-1-108-44746-1.OCLC 1222779588.{{citebook}}:|last=hasgenericname(help) BenkertO,HippiusH.KompendiumderPsychiatrischenPharmakotherapie(inGerman)(4th ed.).SpringerVerlag. BandelowB,BleichS,KroppS.HandbuchPsychopharmaka(inGerman)(2nd ed.).Hogrefe. DeanL(2016)."ClozapineTherapyandCYP2D6,CYP1A2,andCYP3A4Genotypes".InPrattVM,McLeodHL,RubinsteinWS,et al.(eds.).MedicalGeneticsSummaries.NationalCenterforBiotechnologyInformation(NCBI).PMID 28520368.BookshelfID:NBK367795. Externallinks[edit] "Clozapine".DrugInformationPortal.U.S.NationalLibraryofMedicine. "ClozapineRiskEvaluationandMitigationStrategy(REMS)requirementswillchangeonNovember15,2021".U.S.FoodandDrugAdministration(FDA).29July2021. "ClozapineREMSModificationFrequentlyAskedQuestions".U.S.FoodandDrugAdministration(FDA).29July2021. vteAntipsychotics(N05A)Typical Butyrophenones:Benperidol Bromperidol Bromperidoldecanoate Droperidol Haloperidol# Haloperidoldecanoate Moperone Pipamperone Spiperone Timiperone Trifluperidol Diphenylbutylpiperidines:Fluspirilene Penfluridol Pimozide Phenothiazines:Acepromazine Acetophenazine Butaperazine Carphenazine(carfenazine)‡ Chlorpromazine Cyamemazine Dixyrazine Fluphenazine Fluphenazinedecanoate Fluphenazineenanthate Levomepromazine(methotrimeprazine) Mesoridazine Perazine Periciazine Perphenazine BL-1020 Perphenazinedecanoate Perphenazineenanthate Piperacetazine Pipotiazine Pipotiazinepalmitate Pipotiazineundecylenate Prochlorperazine Promazine Sulforidazine Thiopropazate Thioproperazine Thioridazine Trifluoperazine Triflupromazine Thioxanthenes:Chlorprothixene Clopenthixol Clopenthixoldecanoate Flupentixol Flupentixoldecanoate Tiotixene(thiothixene) Zuclopenthixol Zuclopenthixolacetate Zuclopenthixoldecanoate Disputed Benzamides:Amisulpride Levosulpiride Nemonapride Remoxipride‡ Sulpiride Sultopride Tiapride Veralipride‡ Butyrophenones:Melperone Tricyclics:Carpipramine Clocapramine Clorotepine Clotiapine Loxapine Mosapramine Oxyprothepindecanoate Others:Molindone Atypical Benzisoxazole/benzisothiazoles:Iloperidone Lurasidone Paliperidone Paliperidonepalmitate Perospirone Risperidone# Ziprasidone Butyrophenones:Lumateperone Phenylpiperazines/quinolinones:Aripiprazole Aripiprazolelauroxil Brilaroxazine† Brexpiprazole Cariprazine Tricyclics:Asenapine Clozapine# Olanzapine Quetiapine Zotepine Others:Blonanserin Pimavanserin Sertindole Others Monoamine-depletingagents:Oxypertine Reserpine Tetrabenazine Others/unknown:Azacyclonol #WHO-EM ‡Withdrawnfrommarket Clinicaltrials: †PhaseIII §NevertophaseIII vteMoodstabilizersAnticonvulsants Carbamazepine Lamotrigine Oxcarbazepine Valproate Valnoctamide Valproatepivoxil Valpromide Atypicalantipsychotics Aripiprazole Asenapine Cariprazine Clozapine Lurasidone Olanzapine(+fluoxetine) Paliperidone Quetiapine Risperidone Ziprasidone Others Ketamine Lithium(lithiumacetate,lithiumcarbonate,lithiumchloride,lithiumcitrate,lithiumhydroxide,lithiumorotate) Omega-3fattyacids(docosahexaenoicacid,eicosapentaenoicacid) Pharmacodynamics vteAdrenergicreceptormodulatorsα1Agonists 6-FNE Amidephrine Buspirone Cirazoline Corbadrine Deoxyepinephrine(epinine,N-methyldopamine) Desglymidodrine Dexisometheptene Dipivefrine Dopamine Droxidopa(L-DOPS) Epinephrine Etilefrine Etilevodopa Ethylnorepinephrine Ibopamine Indanidine Isometheptene L-DOPA(levodopa) L-Phenylalanine L-Tyrosine Melevodopa Metaraminol Methoxamine Methyldopa Midodrine Naphazoline Norepinephrine Octopamine Oxymetazoline Phenylephrine Phenylpropanolamine Synephrine Tetryzoline Tiamenidine XP21279 Xylometazoline Antagonists Abanoquil Ajmalicine Alfuzosin Anisodamine Anisodine Atiprosin Atypicalantipsychotics(e.g.,brexpiprazole,clozapine,olanzapine,quetiapine,risperidone) Benoxathian Betablockers(e.g.,adimolol,amosulalol,arotinolol,carvedilol,eugenodilol,labetalol) Buflomedil Bunazosin Corynanthine Dapiprazole Domesticine Doxazosin Ergolines(e.g.,acetergamine,ergotamine,dihydroergotamine,lisuride,nicergoline,terguride) Etoperidone Fenspiride Hydroxyzine Indoramin Ketanserin L-765,314 mCPP Mepiprazole Metazosin Monatepil Moxisylyte Naftopidil Nantenine Neldazosin Niaprazine Niguldipine Pardoprunox Pelanserin Perlapine Phendioxan Phenoxybenzamine Phentolamine Phenylpiperazineantidepressants(e.g.,hydroxynefazodone,nefazodone,trazodone,triazoledione) Piperoxan Prazosin Quinazosin Quinidine Silodosin Spegatrine Spiperone Talipexole Tamsulosin Terazosin Tiodazosin Tolazoline Tetracyclicantidepressants(e.g.,amoxapine,maprotiline,mianserin) Tricyclicantidepressants(e.g.,amitriptyline,clomipramine,doxepin,imipramine,trimipramine) Trimazosin Typicalantipsychotics(e.g.,chlorpromazine,fluphenazine,loxapine,thioridazine) Urapidil WB-4101 Zolertine α2Agonists (R)-3-Nitrobiphenyline 4-NEMD 6-FNE Amitraz Apraclonidine Brimonidine Clonidine Corbadrine Deoxyepinephrine(epinine,N-methyldopamine) Detomidine Dexmedetomidine Dihydroergotamine Dipivefrine Dopamine Droxidopa(L-DOPS) Etilevodopa Ergotamine Epinephrine Etilefrine Ethylnorepinephrine Guanabenz Guanfacine Guanoxabenz L-DOPA(levodopa) L-Phenylalanine L-Tyrosine Ibopamine Lofexidine Medetomidine Melevodopa Methyldopa Mivazerol Moxonidine Naphazoline Norepinephrine Oxymetazoline Phenylpropanolamine Piperoxan Rezatomidine Rilmenidine Romifidine Talipexole Tasipimidine Tetrahydrozoline Tiamenidine Tizanidine Tolonidine Urapidil Vatinoxan XP21279 Xylazine Xylometazoline Antagonists 1-PP Adimolol Amesergide Aptazapine Atipamezole Atypicalantipsychotics(e.g.,asenapine,brexpiprazole,clozapine,lurasidone,olanzapine,paliperidone,quetiapine,risperidone,zotepine) Azapirones(e.g.,buspirone,gepirone,ipsapirone,tandospirone) BRL-44408 Buflomedil Cirazoline Efaroxan Esmirtazapine Fenmetozole Fluparoxan Idazoxan Ketanserin Lisuride mCPP Mianserin Mirtazapine NAN-190 Pardoprunox Phentolamine Phenoxybenzamine Piperoxan Piribedil Rauwolscine Rotigotine Setiptiline Spegatrine Spiroxatrine Sunepitron Terguride Tolazoline Typicalantipsychotics(e.g.,chlorpromazine,fluphenazine,loxapine,thioridazine) Yohimbine βAgonists Abediterol Alifedrine Amibegron Arbutamine Arformoterol Arotinolol BAAM Bambuterol Befunolol Bitolterol Broxaterol Buphenine Carbuterol Carmoterol Cimaterol Clenbuterol Colterol Corbadrine Denopamine Deoxyepinephrine(epinine,N-methyldopamine) Dipivefrine Dobutamine Dopamine Dopexamine Droxidopa(L-DOPS) Epinephrine Etafedrine Etilefrine Etilevodopa Ethylnorepinephrine Eugenodilol Fenoterol Formoterol Hexoprenaline Higenamine Ibopamine Indacaterol Isoetarine Isoprenaline Isoxsuprine L-DOPA(levodopa) L-Phenylalanine L-Tyrosine Levosalbutamol Lubabegron Mabuterol Melevodopa Methoxyphenamine Methyldopa Mirabegron Norepinephrine Orciprenaline Oxyfedrine PF-610355 Phenylpropanolamine Pirbuterol Prenalterol Ractopamine Procaterol Reproterol Rimiterol Ritodrine Salbutamol Salmeterol Solabegron Terbutaline Tretoquinol Tulobuterol Vibegron Vilanterol Xamoterol XP21279 Zilpaterol Zinterol Antagonists Acebutolol Adaprolol Adimolol Afurolol Alprenolol Alprenoxime Amosulalol Ancarolol Arnolol Arotinolol Atenolol Befunolol Betaxolol Bevantolol Bisoprolol Bopindolol Bornaprolol Brefonalol Bucindolol Bucumolol Bufetolol Bufuralol Bunitrolol Bunolol Bupranolol Butaxamine Butidrine Butofilolol Capsinolol Carazolol Carpindolol Carteolol Carvedilol Celiprolol Cetamolol Cicloprolol Cinamolol Cloranolol Cyanopindolol Dalbraminol Dexpropranolol Diacetolol Dichloroisoprenaline Dihydroalprenolol Dilevalol Diprafenone Draquinolol Ecastolol Epanolol Ericolol Ersentilide Esatenolol Esprolol Eugenodilol Exaprolol Falintolol Flestolol Flusoxolol Hydroxycarteolol Hydroxytertatolol ICI-118,551 Idropranolol Indenolol Indopanolol Iodocyanopindolol Iprocrolol Isoxaprolol Isamoltane Labetalol Landiolol Levobetaxolol Levobunolol Levomoprolol Medroxalol Mepindolol Metipranolol Metoprolol Moprolol Nadolol Nadoxolol Nebivolol Nifenalol Nipradilol Oxprenolol Pacrinolol Pafenolol Pamatolol Pargolol Penbutolol Pindolol Practolol Primidolol Procinolol Pronethalol Propafenone Propranolol Ridazolol Ronactolol Soquinolol Sotalol Spirendolol SR59230A Sulfinalol Talinolol Tazolol Tertatolol Tienoxolol Tilisolol Timolol Tiprenolol Tolamolol Toliprolol Xibenolol Xipranolol Seealso:Receptor/signalingmodulators Dopaminergics Serotonergics Monoaminereuptakeinhibitors Monoaminereleasingagents Monoaminemetabolismmodulators Monoamineneurotoxins vteDopaminereceptormodulatorsD1-likeAgonists Benzazepines:6-Br-APB Fenoldopam SKF-38,393 SKF-77,434 SKF-81,297 SKF-82,958 SKF-83,959 Trepipam Zelandopam Ergolines:Cabergoline CY-208,243 Dihydroergocryptine LEK-8829 Lisuride Pergolide Terguride Dihydrexidinederivatives:A-77636 A-86929 Adrogolide(ABT-431,DAS-431) Dihydrexidine Dinapsoline Dinoxyline Doxanthrine Phenethylamines:BCO-001 Deoxyepinephrine(N-methyldopamine,epinine) Dopexamine Etilevodopa Ibopamine L-DOPA(levodopa) Melevodopa L-Phenylalanine L-Tyrosine XP21279 Others:A-68930 Apomorphine Isocorypalmine Nuciferine PF-6649751 PF6669571 Propylnorapomorphine Rotigotine SKF-89,145 SKF-89,626 Stepholidine Tavapadon Tetrahydropalmatine PAMs DETQ DPTQ Mevidalen(LY3154207) Antagonists Typicalantipsychotics:Butaclamol Chlorpromazine Chlorprothixene Flupentixol(flupenthixol)(+melitracen) Fluphenazine Loxapine Perphenazine(+amitriptyline) Pifluthixol Thioridazine Thiothixene Trifluoperazine(+tranylcypromine) Zuclopenthixol Atypicalantipsychotics:Asenapine Clorotepine Clotiapine Clozapine DHA-clozapine Fluperlapine Iloperidone Norclozapine Norquetiapine Olanzapine(+fluoxetine) Paliperidone Quetiapine Risperidone Tefludazine Zicronapine Ziprasidone Zotepine Others:Berupipam Ecopipam EEDQ Metitepine(methiothepin) Odapipam Perlapine SCH-23390 D2-likeAgonists Adamantanes:Amantadine Memantine Rimantadine Aminotetralins:5-OH-DPAT 7-OH-DPAT 8-OH-PBZI Rotigotine UH-232 Ergolines:Bromocriptine Cabergoline Chanoclavine Dihydroergocryptine Epicriptine Ergocornine Lergotrile Lisuride LSD Pergolide Terguride Dihydrexidinederivatives:2-OH-NPA Ciladopa Dihydrexidine Dinoxyline N,N-Propyldihydrexidine Phenethylamines:Deoxyepinephrine(N-methyldopamine,epinine) Dopexamine Etilevodopa Ibopamine L-DOPA(levodopa) L-Phenylalanine L-Tyrosine Melevodopa XP21279 Atypicalantipsychotics:Alentemol(U-66444B) Aripiprazole(+sertraline) Aripiprazolelauroxil Bifeprunox Brexpiprazole Brilaroxazine Cariprazine F-15063 Lumateperone Norclozapine Others:3-PPP A-412997 ABT-670 ABT-724 Adrafinil Aplindore Apomorphine Arketamine Armodafinil BP-897 Captodiame CP-226,269 Dizocilpine Esketamine Flibanserin Ketamine Mesulergine Modafinil OSU-6162 Pardoprunox PD-128,907 PD-168,077 PF-219,061 PF-592,379 Phencyclidine Piribedil Pramipexole Preclamol Propylnorapomorphine Pukateine Quinagolide Quinelorane Quinpirole RDS-127 Ro10-5824 Ropinirole Roxindole SalvinorinA SKF-83,959 Sumanirole Talipexole Umespirone WAY-100,635 Antagonists Typicalantipsychotics:Acepromazine Acetophenazine Azaperone Benperidol Bromperidol Butaclamol Butaperazine Chloracizine Chlorproethazine Chlorpromazine Chlorprothixene Ciclindole Clopenthixol Clothixamide Clopimozide Droperidol Fluacizine Fluanisone Flucindole Fluotracen Flupentixol(flupenthixol)(+melitracen) Fluphenazine Fluprothixene Fluspirilene Haloperidol Homopipramol Lenperone Levomepromazine(methotrimeprazine) Levosulpiride Loxapine Mesoridazine Moperone Naranol Nemonapride Penfluridol Perathiepin Perazine Pericyazine(periciazine) Perphenazine(+amitriptyline) Piflutixol(pifluthixol) Pimozide Pipamperone Preclamol Prochlorperazine Promazine Prothipendyl Spiperone(spiroperidol) Sulforidazine Sulpiride Sultopride Teflutixol Thiopropazate Thioproperazine Thioridazine Thiothixene Timiperone Trifluoperazine(+tranylcypromine) Triflupromazine Trifluperidol Zetidoline Zuclopenthixol Atypicalantipsychotics:Amisulpride Asenapine BL-1020 Blonanserin Carpipramine Cinuperone Clocapramine Clorotepine Clotiapine(clothiapine) Clozapine Cyamemazine DHA-clozapine Dixyrazine Elopiprazole Flumezapine Fluperlapine Gevotroline Iloperidone Lurasidone Mazapertine Melperone Molindone Mosapramine Ocaperidone Olanzapine(+fluoxetine) Paliperidone Perospirone Piperacetazine Pipotiazine Piquindone Quetiapine Remoxipride Risperidone Sertindole Tefludazine Tenilapine Tiospirone Veralipride Zicronapine Ziprasidone Zotepine Antiemetics/gastroprokinetics/sedatives:Aceprometazine AS-8112 Alimemazine Alizapride Benzquinamide Bromopride Clebopride Deudomperidone Domperidone Eticlopride Hydroxyzine Itopride Metoclopramide Metopimazine Promethazine Thiethylperazine Trimethobenzamide Antidepressants:Amoxapine Nefazodone Opipramol Propiomazine Trimipramine Others:3-PPP Alpiropride Azapride Bromerguride Bromocriptine Buspirone Desmethoxyfallypride EEDQ F-15063 Fallypride Fananserin Fenfluramine Iodobenzamide Isocorypalmine L-741,626 L-745,870 Levofenfluramine LEK-8829 Metergoline Metitepine(methiothepin) N-Methylspiperone Nafadotride Nuciferine PNU-99,194 Pridopidine Raclopride Sarizotan SB-277,011-A Seridopidine Sonepiprazole Spiroxatrine Stepholidine SV-293 Terguride Tetrahydropalmatine Tiapride UH-232 Yohimbine Seealso:Receptor/signalingmodulators Adrenergics Serotonergics Monoaminereuptakeinhibitors Monoaminereleasingagents Monoaminemetabolismmodulators Monoamineneurotoxins vteHistaminereceptormodulatorsH1Agonists 2-Pyridylethylamine Betahistine Histamine HTMT L-Histidine UR-AK49 Antagonists First-generation:4-Methyldiphenhydramine Alimemazine Antazoline Azatadine Bamipine Benzatropine(benztropine) Bepotastine Bromazine Brompheniramine Buclizine Captodiame Carbinoxamine Chlorcyclizine Chloropyramine Chlorothen Chlorphenamine Chlorphenoxamine Cinnarizine Clemastine Clobenzepam Clocinizine Cloperastine Cyclizine Cyproheptadine Dacemazine Decloxizine Deptropine Dexbrompheniramine Dexchlorpheniramine Dimenhydrinate Dimetindene Diphenhydramine Diphenylpyraline Doxylamine Embramine Etodroxizine Etybenzatropine(ethylbenztropine) Etymemazine Fenethazine Flunarizine Histapyrrodine Homochlorcyclizine Hydroxyethylpromethazine Hydroxyzine Isopromethazine Isothipendyl Meclozine Medrylamine Mepyramine(pyrilamine) Mequitazine Methafurylene Methapyrilene Methdilazine Moxastine Orphenadrine Oxatomide Oxomemazine Perlapine Phenindamine Pheniramine Phenyltoloxamine Pimethixene Piperoxan Pipoxizine Promethazine Propiomazine Pyrrobutamine Talastine Thenalidine Thenyldiamine Thiazinamium Thonzylamine Tolpropamine Tripelennamine Triprolidine Second/third-generation:Acrivastine Alinastine Astemizole Azelastine Bamirastine Barmastine Bepiastine Bepotastine Bilastine Cabastinen Carebastine Cetirizine Clemastine Clemizole Clobenztropine Desloratadine Dorastine Ebastine Efletirizine Emedastine Epinastine Fexofenadine Flezelastine Ketotifen Latrepirdine Levocabastine Levocetirizine Linetastine Loratadine Mapinastine Mebhydrolin Mizolastine Moxastine Noberastine Octastine Olopatadine Perastine Pibaxizine Piclopastine Quifenadine(phencarol) Rocastine Rupatadine Setastine Sequifenadine(bicarphen) Talastine Temelastine Terfenadine Vapitadine Zepastine Others:Atypicalantipsychotics(e.g.,aripiprazole,asenapine,brexpiprazole,brilaroxazine,clozapine,iloperidone,olanzapine,paliperidone,quetiapine,risperidone,ziprasidone,zotepine) Phenylpiperazineantidepressants(e.g.,hydroxynefazodone,nefazodone,trazodone,triazoledione) Tetracyclicantidepressants(e.g.,amoxapine,loxapine,maprotiline,mianserin,mirtazapine,oxaprotiline) Tricyclicantidepressants(e.g.,amitriptyline,butriptyline,clomipramine,desipramine,dosulepin(dothiepin),doxepin,imipramine,iprindole,lofepramine,nortriptyline,protriptyline,trimipramine) Typicalantipsychotics(e.g.,chlorpromazine,flupenthixol,fluphenazine,loxapine,perphenazine,prochlorperazine,thioridazine,thiothixene) Unknown/unsorted:Azanator Belarizine Elbanizine Flotrenizine GSK1004723 Napactadine Tagorizine Trelnarizine Trenizine H2Agonists Amthamine Betazole Dimaprit Histamine HTMT Impromidine L-Histidine UR-AK49 Antagonists Bisfentidine Burimamide Cimetidine Dalcotidine Donetidine Ebrotidine Etintidine Famotidine Isolamtidine Lafutidine Lamtidine Lavoltidine(loxtidine) Lupitidine Metiamide Mifentidine Niperotidine Nizatidine Osutidine Oxmetidine Pibutidine Quisultazine(quisultidine) Ramixotidine Ranitidine Roxatidine Sufotidine Tiotidine Tuvatidine Venritidine Xaltidine Zolantidine H3Agonists α-Methylhistamine Cipralisant Histamine Imetit Immepip Immethridine L-Histidine Methimepip Proxyfan Antagonists A-349821 A-423579 ABT-239 ABT-652 AZD5213 Bavisant Betahistine Burimamide Ciproxifan Clobenpropit Conessine Enerisant GSK-189254 Impentamine Iodophenpropit Irdabisant JNJ-5207852 NNC38-1049 PF-03654746 Pitolisant SCH-79687 Thioperamide VUF-5681 H4Agonists 4-Methylhistamine α-Methylhistamine Histamine L-Histidine OUP-16 VUF-8430 Antagonists JNJ-7777120 Mianserin Seliforant Thioperamide Toreforant VUF-6002 Seealso:Receptor/signalingmodulators•Monoaminemetabolismmodulators•Monoaminereuptakeinhibitors vteMuscarinicacetylcholinereceptormodulatorsmAChRsAgonists 77-LH-28-1 AC-42 AC-260,584 Aceclidine Acetylcholine AF30 AF150(S) AF267B Alvameline AQRA-741 Arecoline Bethanechol Bevonium Butyrylcholine Carbachol CDD-0034 CDD-0078 CDD-0097 CDD-0098 CDD-0102 Cevimeline Choline cis-Dioxolane Clozapine Desmethylclozapine(norclozapine) Ethoxysebacylcholine Itameline LY-593,039 L-689,660 LY-2,033,298 McNA343 Methacholine Milameline Muscarine NGX-267 Ocvimeline Oxotremorine PD-151,832 Pilocarpine RS86 Sabcomeline SDZ210-086 Sebacylcholine Suberyldicholine Talsaclidine Tazomeline Thiopilocarpine Vedaclidine VU-0029767 VU-0090157 VU-0152099 VU-0152100 VU-0238429 WAY-132,983 Xanomeline YM-796 Antagonists 3-Quinuclidinylbenzilate 4-DAMP Aclidiniumbromide(+formoterol) Abediterol AF-DX250 AF-DX384 Ambutoniumbromide Anisodamine Anisodine Antihistamines(first-generation)(e.g.,brompheniramine,buclizine,captodiame,chlorphenamine(chlorpheniramine),cinnarizine,clemastine,cyproheptadine,dimenhydrinate,dimetindene,diphenhydramine,doxylamine,meclizine,mequitazine,perlapine,phenindamine,pheniramine,phenyltoloxamine,promethazine,propiomazine,triprolidine) AQ-RA741 Atropine Atropinemethonitrate Atypicalantipsychotics(e.g.,clozapine,fluperlapine,olanzapine(+fluoxetine),rilapine,quetiapine,tenilapine,zotepine) Benactyzine Benzatropine(benztropine) Benzilone Benzilylcholinemustard Benzydamine BIBN99 Biperiden Bornaprine Camylofin CAR-226,086 CAR-301,060 CAR-302,196 CAR-302,282 CAR-302,368 CAR-302,537 CAR-302,668 Caramiphen Cimetropiumbromide Clidiniumbromide Cloperastine CS-27349 Cyclobenzaprine Cyclopentolate Darifenacin DAU-5884 Desfesoterodine Dexetimide DIBD Dicycloverine(dicyclomine) Dihexyverine Difemerine Diphemanilmetilsulfate Ditran Drofenine EA-3167 EA-3443 EA-3580 EA-3834 Emeproniumbromide Etanautine Etybenzatropine(ethybenztropine) Fenpiverinium Fentoniumbromide Fesoterodine Flavoxate Glycopyrroniumbromide(+beclometasone/formoterol,+indacaterol) Hexahydrodifenidol Hexahydrosiladifenidol Hexbutinol Hexocyclium Himbacine HL-031,120 Homatropine Imidafenacin Ipratropiumbromide(+salbutamol) Isopropamide J-104,129 Hyoscyamine Mambatoxin3 Mambatoxin7 Mazaticol Mebeverine Meladrazine Mepenzolate Methantheline Methoctramine Methylatropine Methylhomatropine Methylscopolamine Metixene Muscarinictoxin7 N-Ethyl-3-piperidylbenzilate N-Methyl-3-piperidylbenzilate Nefopam Octatropinemethylbromide(anisotropinemethylbromide) Orphenadrine Otenzepad(AF-DX116) Otiloniumbromide Oxapiumiodide Oxitropiumbromide Oxybutynin Oxyphencyclimine Oxyphenoniumbromide PBID PD-102,807 PD-0298029 Penthienate Pethidine pFHHSiD Phenglutarimide Phenyltoloxamine Pipenzolatebromide Piperidolate Pirenzepine Piroheptine Pizotifen Poldine Pridinol Prifiniumbromide Procyclidine Profenamine(ethopropazine) Propanthelinebromide Propiverine Quinidine 3-Quinuclidinylthiochromane-4-carboxylate Revefenacin Rociverine RU-47,213 SCH-57,790 SCH-72,788 SCH-217,443 Scopolamine(hyoscine) Scopolaminebutylbromide(hyoscinebutylbromide) Silahexacyclium Sofpironiumbromide Solifenacin SSRIs(e.g.,femoxetine,paroxetine) Telenzepine Terodiline Tetracyclicantidepressants(e.g.,amoxapine,maprotiline,mianserin,mirtazapine) Tiemoniumiodide Timepidiumbromide Tiotropiumbromide Tiquiziumbromide Tofenacin Tolterodine Tricyclicantidepressants(e.g.,amitriptyline(+perphenazine),amitriptylinoxide,butriptyline,cidoxepin,clomipramine,desipramine,desmethyldesipramine,dibenzepin,dosulepin(dothiepin),doxepin,imipramine,lofepramine,nitroxazepine,northiaden(desmethyldosulepin),nortriptyline,protriptyline,quinupramine,trimipramine) Tridihexethyl Trihexyphenidyl Trimebutine Tripitamine(tripitramine) Tropacine Tropatepine Tropicamide Trospiumchloride Typicalantipsychotics(e.g.,chlorpromazine,chlorprothixene,cyamemazine(cyamepromazine),loxapine,mesoridazine,thioridazine) Umeclidiniumbromide(+vilanterol) WIN-2299 Xanomeline Zamifenacin Precursors(andprodrugs) Acetyl-coA Adafenoxate Choline(lecithin) Citicoline Cyprodenate Dimethylethanolamine Glycerophosphocholine Meclofenoxate(centrophenoxine) Phosphatidylcholine Phosphatidylethanolamine Phosphorylcholine Pirisudanol Seealso:Receptor/signalingmodulators•Nicotinicacetylcholinereceptormodulators•Acetylcholinemetabolism/transportmodulators vteSerotoninreceptormodulators5-HT15-HT1A Agonists:8-OH-DPAT Adatanserin Amphetamine Antidepressants(e.g.,etoperidone,hydroxynefazodone,nefazodone,trazodone,triazoledione,vilazodone,vortioxetine) Atypicalantipsychotics(e.g.,aripiprazole,asenapine,brexpiprazole,cariprazine,clozapine,lurasidone,quetiapine,ziprasidone) Azapirones(e.g.,buspirone,eptapirone,gepirone,perospirone,tandospirone) BayR1531 Befiradol BMY-14802 Cannabidiol Dimemebfe Dopamine Ebalzotan Eltoprazine Enciprazine Ergolines(e.g.,bromocriptine,cabergoline,dihydroergotamine,ergotamine,lisuride,LSD,methylergometrine(methylergonovine),methysergide,pergolide) F-11461 F-12826 F-13714 F-14679 F-15063 F-15,599 Flesinoxan Flibanserin Flumexadol Hypidone Lesopitron LY-293284 LY-301317 mCPP MKC-242 Naluzotan NBUMP Osemozotan Oxaflozane Pardoprunox Piclozotan Rauwolscine Repinotan Roxindole RU-24,969 S-14,506 S-14671 S-15535 Sarizotan Serotonin(5-HT) SSR-181507 Sunepitron Tryptamines(e.g.,5-CT,5-MeO-DMT,5-MT,bufotenin,DMT,indorenate,N-Me-5-HT,psilocin,psilocybin) TGBA01AD U-92,016-A Urapidil Vilazodone Xaliproden Yohimbine Antagonists:Atypicalantipsychotics(e.g.,iloperidone,risperidone,sertindole) AV965 Betablockers(e.g.,alprenolol,carteolol,cyanopindolol,iodocyanopindolol,isamoltane,oxprenolol,penbutolol,pindobind,pindolol,propranolol,tertatolol) BMY-7,378 CSP-2503 Dotarizine Ergolines(e.g.,metergoline) FCE-24379 Flopropione GR-46611 Isamoltane Lecozotan Mefway Metitepine(methiothepin) MIN-117(WF-516) MPPF NAN-190 Robalzotan S-15535 SB-649,915 SDZ216-525 Spiperone Spiramide Spiroxatrine UH-301 WAY-100135 WAY-100635 Xylamidine Unknown/unsorted:Acetryptine Carvedilol Ergolines(e.g.,ergometrine(ergonovine)) 5-HT1B Agonists:Anpirtoline CGS-12066A CP-93129 CP-94253 CP-122,288 CP-135807 Eltoprazine Ergolines(e.g.,bromocriptine,dihydroergotamine,ergotamine,methylergometrine(methylergonovine),methysergide,pergolide) mCPP RU-24,969 Serotonin(5-HT) Triptans(e.g.,avitriptan,donitriptan,eletriptan,sumatriptan,zolmitriptan) TFMPP Tryptamines(e.g.,5-BT,5-CT,5-MT,DMT) Vortioxetine Antagonists:AR-A000002 Betablockers(e.g.,alprenolol,carteolol,isamoltane,oxprenolol,penbutolol,propranolol,tertatolol) Elzasonan Ergolines(e.g.,metergoline) GR-127935 Isamoltane LY-393558 Metitepine(methiothepin) SB-216641 SB-224289 SB-236057 Yohimbine Unknown/unsorted:Ergolines(e.g.,cabergoline,ergometrine(ergonovine),lisuride) 5-HT1D Agonists:CP-122,288 CP-135807 CP-286601 Ergolines(e.g.,bromocriptine,cabergoline,dihydroergotamine,ergotamine,LSD,methysergide) GR-46611 L-694247 L-772405 mCPP PNU-109291 PNU-142633 Serotonin(5-HT) TGBA01AD Triptans(e.g.,almotriptan,avitriptan,donitriptan,eletriptan,frovatriptan,naratriptan,rizatriptan,sumatriptan,zolmitriptan) Tryptamines(e.g.,5-BT,5-CT,5-Et-DMT,5-MT,5-(nonyloxy)tryptamine,DMT) Antagonists:Alniditan BRL-15,572 Elzasonan Ergolines(e.g.,metergoline) GR-127935 Ketanserin LY-310762 LY-367642 LY-393558 LY-456219 LY-456220 Metitepine(methiothepin) Mianserin Ritanserin Yohimbine Ziprasidone Unknown/unsorted:Acetryptine Ergolines(e.g.,lisuride,lysergol,pergolide) 5-HT1E Agonists:BRL-54443 Ergolines(e.g.,methysergide) Serotonin(5-HT) Triptans(e.g.,eletriptan) Tryptamines(e.g.,tryptamine) Antagonists:Metitepine(methiothepin) Unknown/unsorted:Ergolines(e.g.,ergometrine(ergonovine),lysergol,methylergometrine(methylergonovine) 5-HT1F Agonists:BRL-54443 CP-122,288 Ergolines(e.g.,bromocriptine,lysergol,methylergometrine(methylergonovine)methysergide) Lasmiditan LY-334370 Serotonin(5-HT) Triptans(e.g.,eletriptan,naratriptan,sumatriptan) Tryptamines(e.g.,5-MT) Antagonists:Metitepine(methiothepin) Mianserin 5-HT25-HT2A Agonists:25H/NBseries(e.g.,25I-NBF,25I-NBMD,25I-NBOH,25I-NBOMe,25B-NBOMe,25C-NBOMe,25TFM-NBOMe,2CBCB-NBOMe,25CN-NBOH,2CBFly-NBOMe) 2Cs(e.g.,2C-B,2C-E,2C-I,2C-T-2,2C-T-7,2C-T-21) 2C-B-FLY 2CB-Ind 5-Methoxytryptamines(5-MeO-DET,5-MeO-DiPT,5-MeO-DMT,5-MeO-DPT,5-MT) α-Alkyltryptamines(e.g.,5-Cl-αMT,5-Fl-αMT,5-MeO-αET,5-MeO-αMT,α-Me-5-HT,αET,αMT) AL-34662 AL-37350A Bromo-DragonFLY Dimemebfe DMBMPP DOx(e.g.,DOB,DOC,DOI,DOM) Efavirenz Ergolines(e.g.,1P-LSD,ALD-52,bromocriptine,cabergoline,ergine(LSA),ergometrine(ergonovine),ergotamine,lisuride,LA-SS-Az,LSB,LSD,LSD-Pip,LSH,LSP,methylergometrine(methylergonovine),pergolide) Flumexadol IHCH-7113 Jimscaline Lorcaserin MDxx(e.g.,MDA(tenamfetamine),MDMA(midomafetamine),MDOH,MMDA) O-4310 Oxaflozane PHA-57378 PNU-22394 PNU-181731 RH-34 Phenethylamines(e.g.,lophophine,mescaline) Piperazines(e.g.,BZP,quipazine,TFMPP) Serotonin(5-HT) TCB-2 TFMFly Tryptamines(e.g.,5-BT,5-CT,bufotenin,DET,DiPT,DMT,DPT,psilocin,psilocybin,tryptamine) Antagonists:5-I-R91150 5-MeO-NBpBrT AC-90179 Adatanserin Altanserin Antihistamines(e.g.,cyproheptadine,hydroxyzine,ketotifen,perlapine) AMDA Atypicalantipsychotics(e.g.,amperozide,aripiprazole,asenapine,blonanserin,brexpiprazole,carpipramine,clocapramine,clorotepine,clozapine,fluperlapine,gevotroline,iloperidone,lurasidone,melperone,mosapramine,ocaperidone,olanzapine,paliperidone,quetiapine,risperidone,sertindole,zicronapine,ziprasidone,zotepine) Chlorprothixene Cinanserin CSP-2503 Deramciclane Dotarizine Eplivanserin Ergolines(e.g.,amesergide,LY-53857,LY-215,840,mesulergine,metergoline,methysergide,sergolexole) Fananserin Flibanserin Glemanserin Irindalone Ketanserin KML-010 Landipirdine LY-393558 mCPP Medifoxamine Metitepine(methiothepin) MIN-117(WF-516) Naftidrofuryl Nantenine Nelotanserin Opiranserin(VVZ-149) Pelanserin Phenoxybenzamine Pimavanserin Pirenperone Pizotifen Pruvanserin Rauwolscine Ritanserin Roluperidone S-14671 Sarpogrelate Serotoninantagonistsandreuptakeinhibitors(e.g.,etoperidone,hydroxynefazodone,lubazodone,mepiprazole,nefazodone,triazoledione,trazodone) SR-46349B TGBA01AD Teniloxazine Temanogrel Tetracyclicantidepressants(e.g.,amoxapine,aptazapine,esmirtazapine,maprotiline,mianserin,mirtazapine) Tricyclicantidepressants(e.g.,amitriptyline) Typicalantipsychotics(e.g.,chlorpromazine,fluphenazine,haloperidol,loxapine,perphenazine,pimozide,pipamperone,prochlorperazine,setoperone,spiperone,spiramide,thioridazine,thiothixene,trifluoperazine) Volinanserin Xylamidine Yohimbine Unknown/unsorted:Ergolines(e.g.,dihydroergotamine,nicergoline) 5-HT2B Agonists:4-Methylaminorex Aminorex Amphetamines(e.g.,chlorphentermine,cloforex,dexfenfluramine,fenfluramine,levofenfluramine,norfenfluramine) BW-723C86 DOx(e.g.,DOB,DOC,DOI,DOM) Ergolines(e.g.,cabergoline,dihydroergocryptine,dihydroergotamine,ergotamine,methylergometrine(methylergonovine),methysergide,pergolide) Lorcaserin MDxx(e.g.,MDA(tenamfetamine),MDMA(midomafetamine),MDOH,MMDA) Piperazines(e.g.,TFMPP) PNU-22394 Ro60-0175 Serotonin(5-HT) Tryptamines(e.g.,5-BT,5-CT,5-MT,α-Me-5-HT,bufotenin,DET,DiPT,DMT,DPT,psilocin,psilocybin,tryptamine) Antagonists:Agomelatine Atypicalantipsychotics(e.g.,amisulpride,aripiprazole,asenapine,brexpiprazole,cariprazine,clozapine,N-desalkylquetiapine(norquetiapine),N-desmethylclozapine(norclozapine),olanzapine,pipamperone,quetiapine,risperidone,ziprasidone) Cyproheptadine EGIS-7625 Ergolines(e.g.,amesergide,bromocriptine,lisuride,LY-53857,LY-272015,mesulergine) Ketanserin LY-393558 mCPP Metadoxine Metitepine(methiothepin) Pirenperone Pizotifen Propranolol PRX-08066 Rauwolscine Ritanserin RS-127445 Sarpogrelate SB-200646 SB-204741 SB-206553 SB-215505 SB-221284 SB-228357 SDZSER-082 Tegaserod Tetracyclicantidepressants(e.g.,amoxapine,mianserin,mirtazapine) Trazodone Typicalantipsychotics(e.g.,chlorpromazine) TIK-301 Yohimbine Unknown/unsorted:Ergolines(e.g.,ergometrine(ergonovine)) 5-HT2C Agonists:2Cs(e.g.,2C-B,2C-E,2C-I,2C-T-2,2C-T-7,2C-T-21) 5-Methoxytryptamines(5-MeO-DET,5-MeO-DiPT,5-MeO-DMT,5-MeO-DPT,5-MT) α-Alkyltryptamines(e.g.,5-Cl-αMT,5-Fl-αMT,5-MeO-αET,5-MeO-αMT,α-Me-5-HT,αET,αMT) A-372159 AL-38022A Alstonine CP-809101 Dimemebfe DOx(e.g.,DOB,DOC,DOI,DOM) Ergolines(e.g.,ALD-52,cabergoline,dihydroergotamine,ergine(LSA),ergotamine,lisuride,LA-SS-Az,LSB,LSD,LSD-Pip,LSH,LSP,pergolide) Flumexadol Lorcaserin MDxx(e.g.,MDA(tenamfetamine),MDMA(midomafetamine),MDOH,MMDA) MK-212 ORG-12962 ORG-37684 Oxaflozane PHA-57378 Phenethylamines(e.g.,lophophine,mescaline) Piperazines(e.g.,aripiprazole,BZP,mCPP,quipazine,TFMPP) PNU-22394 PNU-181731 Ro60-0175 Ro60-0213 Serotonin(5-HT) Tryptamines(e.g.,5-BT,5-CT,bufotenin,DET,DiPT,DMT,DPT,psilocin,psilocybin,tryptamine) Vabicaserin WAY-629 WAY-161503 YM-348 Antagonists:Adatanserin Agomelatine Atypicalantipsychotics(e.g.,asenapine,clorotepine,clozapine,fluperlapine,iloperidone,melperone,olanzapine,paliperidone,quetiapine,risperidone,sertindole,ziprasidone,zotepine) Captodiame CEPC Cinanserin Cyproheptadine Deramciclane Desmetramadol Dotarizine Eltoprazine Ergolines(e.g.,amesergide,bromocriptine,LY-53857,LY-215,840,mesulergine,metergoline,methysergide,sergolexole) Etoperidone Fluoxetine FR-260010 Irindalone Ketanserin Ketotifen Latrepirdine(dimebolin) Medifoxamine Metitepine(methiothepin) Nefazodone Pirenperone Pizotifen Propranolol Ritanserin RS-102221 S-14671 SB-200646 SB-206553 SB-221284 SB-228357 SB-242084 SB-243213 SDZSER-082 Tedatioxetine Tetracyclicantidepressants(e.g.,amoxapine,aptazapine,esmirtazapine,maprotiline,mianserin,mirtazapine) TIK-301 Tramadol Trazodone Tricyclicantidepressants(e.g.,amitriptyline,nortriptyline) Typicalantipsychotics(e.g.,chlorpromazine,loxapine,pimozide,pipamperone,thioridazine) Xylamidine Unknown/unsorted:Efavirenz Ergolines(e.g.,ergometrine(ergonovine),methylergometrine(methylergonovine)) 5-HT3–75-HT3 Agonists:Alcohols(e.g.,butanol,ethanol(alcohol),trichloroethanol) m-CPBG Phenylbiguanide Piperazines(e.g.,BZP,mCPP,quipazine) RS-56812 Serotonin(5-HT) SR-57227 SR-57227A Tryptamines(e.g.,2-Me-5-HT,5-CT,bufotenidine(5-HTQ)) Volatiles/gases(e.g.,halothane,isoflurane,toluene,trichloroethane) YM-31636 Antagonists:Alosetron Anpirtoline Arazasetron AS-8112 Atypicalantipsychotics(e.g.,clozapine,olanzapine,quetiapine) Azasetron Batanopride Bemesetron(MDL-72222) Bupropion Cilansetron CSP-2503 Dazopride Dolasetron Galanolactone Granisetron Hydroxybupropion ICS-205930 Lerisetron Memantine Ondansetron Palonosetron Ramosetron Renzapride Ricasetron Tedatioxetine Tetracyclicantidepressants(e.g.,amoxapine,mianserin,mirtazapine) Thujone Tropanserin Tropisetron Typicalantipsychotics(e.g.,loxapine) Volatiles/gases(e.g.,nitrousoxide,sevoflurane,xenon) Vortioxetine Zacopride Zatosetron Unknown/unsorted:LY-53857 Piperazines(e.g.,naphthylpiperazine) 5-HT4 Agonists:5-MT BIMU8 Capeserod Cinitapride Cisapride CJ-033466 Dazopride Metoclopramide Minesapride Mosapride Prucalopride PRX-03140 Renzapride RS-67,333 RS-67,506 Serotonin(5-HT) Tegaserod Usmarapride Velusetrag Zacopride Antagonists:GR-113808 GR-125487 L-Lysine Piboserod RS-39604 RS-67532 SB-203186 SB-204070 5-HT5A Agonists:Ergolines(e.g.,2-Br-LSD(BOL-148),ergotamine,LSD) Serotonin(5-HT) Tryptamines(e.g.,5-CT) Valerenicacid Antagonists:Asenapine Latrepirdine(dimebolin) Metitepine(methiothepin) Ritanserin SB-699551 Unknown/unsorted:Ergolines(e.g.,metergoline,methysergide) Piperazines(e.g.,naphthylpiperazine) 5-HT6 Agonists:Ergolines(e.g.,dihydroergocryptine,dihydroergotamine,ergotamine,lisuride,LSD,mesulergine,metergoline,methysergide) Hypidone Serotonin(5-HT) Tryptamines(e.g.,2-Me-5-HT,5-BT,5-CT,5-MT,Bufotenin,E-6801,E-6837,EMD-386088,EMDT,LY-586713,N-Me-5-HT,ST-1936,tryptamine) WAY-181187 WAY-208466 Antagonists:ABT-354 Atypicalantipsychotics(e.g.,aripiprazole,asenapine,clorotepine,clozapine,fluperlapine,iloperidone,olanzapine,tiospirone) AVN-101 AVN-211 AVN-322 AVN-397 BGC20-760 BVT-5182 BVT-74316 Cerlapirdine EGIS-12,233 GW-742457 Idalopirdine Ketanserin Landipirdine Latrepirdine(dimebolin) Masupirdine Metitepine(methiothepin) MS-245 PRX-07034 Ritanserin Ro04-6790 Ro63-0563 SB-258585 SB-271046 SB-357134 SB-399885 SB-742457 Tetracyclicantidepressants(e.g.,amoxapine,mianserin) Tricyclicantidepressants(e.g.,amitriptyline,clomipramine,doxepin,nortriptyline) Typicalantipsychotics(e.g.,chlorpromazine,loxapine) Unknown/unsorted:Ergolines(e.g.,2-Br-LSD(BOL-148),bromocriptine,lergotrile,pergolide) Piperazines(e.g.,naphthylpiperazine) 5-HT7 Agonists:8-OH-DPAT AS-19 Bifeprunox E-55888 Ergolines(e.g.,LSD) LP-12 LP-44 LP-211 RU-24,969 Sarizotan Serotonin(5-HT) Triptans(e.g.,frovatriptan) Tryptamines(e.g.,5-CT,5-MT,bufotenin,N-Me-5-HT) Antagonists:Atypicalantipsychotics(e.g.,amisulpride,aripiprazole,asenapine,brexpiprazole,clorotepine,clozapine,fluperlapine,olanzapine,risperidone,sertindole,tiospirone,ziprasidone,zotepine) Butaclamol DR-4485 EGIS-12,233 Ergolines(e.g.,2-Br-LSD(BOL-148),amesergide,bromocriptine,cabergoline,dihydroergotamine,ergotamine,LY-53857,LY-215,840,mesulergine,metergoline,methysergide,sergolexole) JNJ-18038683 Ketanserin LY-215,840 Metitepine(methiothepin) Ritanserin SB-258719 SB-258741 SB-269970 SB-656104 SB-656104A SB-691673 SLV-313 SLV-314 Spiperone SSR-181507 Tetracyclicantidepressants(e.g.,amoxapine,maprotiline,mianserin,mirtazapine) Tricyclicantidepressants(e.g.,amitriptyline,clomipramine,imipramine) Typicalantipsychotics(e.g.,acetophenazine,chlorpromazine,chlorprothixene,fluphenazine,loxapine,pimozide) Vortioxetine Unknown/unsorted:Ergolines(e.g.,lisuride,pergolide) Piperazines(e.g.,naphthylpiperazine) Seealso:Receptor/signalingmodulators Adrenergics Dopaminergics Melatonergics Monoaminereuptakeinhibitorsandreleasingagents Monoaminemetabolismmodulators Monoamineneurotoxins vteTricyclicsClasses Acridine Anthracene Dibenzazepine Dibenzocycloheptene Dibenzodiazepine Dibenzothiazepine Dibenzothiepin Dibenzoxazepine Dibenzoxepin Phenothiazine Pyridazinobenzoxazine Pyridinobenzodiazepine Thioxanthene Antidepressants(TCAsandTeCAs) 7-OH-Amoxapine Amezepine Amineptine Amitriptyline Amitriptylinoxide Amoxapine Aptazapine Azepindole Azipramine Batelapine Butriptyline Cianopramine Ciclazindol Ciclopramine Cidoxepin Clomipramine Cotriptyline Cyanodothiepin Demexiptiline Depramine(balipramine) Desipramine(desmethylimipramine) Desmethylclomipramine Desmethyltrimipramine Dibenzepin Dimetacrine Dosulepin(dothiepin) Doxepin Enprazepine Esmirtazapine Fantridone Fluotracen Hepzidine Homopipramol Imipramine Imipraminoxide Intriptyline Iprindole Ketipramine Litracen Lofepramine Losindole Loxapine Maprotiline Mariptiline Mazindol Melitracen Metapramine Mezepine Mianserin Mirtazapine Monometacrine Naranol Nitroxazepine Norbutriptyline Nordoxepin Northiaden(nordosulepin) Nortriptyline(noramitriptyline) Noxiptiline Octriptyline Opipramol Oxaprotiline Pipofezine Pirandamine Propizepine Protriptyline Quinupramine Setiptiline(teciptiline) Spiroxepin Tandamine Tampramine Tianeptine Tienopramine Trimipramine Antihistamines Azatadine Bisulepin Clobenzepam Cyproheptadine Dacemazine Deptropine Desloratadine Epinastine Etymemazine Fenethazine Hydroxyethylpromethazine Isopromethazine Isothipendyl Ketotifen Latrepirdine Loratadine Mebhydrolin Mequitazine Methdilazine Olopatadine Oxomemazine Phenindamine Pimethixene Promethazine Propiomazine Rupatadine Thiazinamium Antipsychotics Acetophenazine Alimemazine Amoxapine Asenapine Butaclamol Butaperazine Carfenazine(carphenazine) Carpipramine Chlorpromazine Chlorprothixene Ciclindole Citatepine Clocapramine Clomacran Clorotepine Clotiapine Clozapine Cyanothepin Doclothepin Docloxythepin Erizepine Flucindole Flumezapine Fluotracen Flupentixol Fluphenazine Gevotroline Homopipramol Isofloxythepin Levomepromazine/Methotrimeprazine Loxapine Lurasidone Maroxepin Meperathiepin Mesoridazine Metiapine Metitepine Metoxepin Mosapramine Naranol Octomethothepin Olanzapine Oxyclothepin Oxyprothepin Pentiapine Peradithiepin Perathiepin Perazine Perphenazine Periciazine Pinoxepin Piperacetazine Pipotiazine Piquindone Prochlorperazine Promazine Prothipendyl Quetiapine Savoxepin/Cipazoxapine Sulforidazine Tenilapine Thiethylperazine Thiopropazate Thioridazine Thiothixene Tilozepine Traboxopine Trifluoperazine Triflupromazine Trifluthepin Zotepine Zuclopenthixol Anticonvulsants Carbamazepine Dizocilpine Eslicarbazepine Eslicarbazepineacetate Etazepine Licarbazepine Oxcarbazepine Oxitriptyline Rispenzepine Others Adosopine Aminopromazine Atiprosin Beloxepin Benzoctamine Carvedilol Cidoxepin Cyclobenzaprine Damotepine Darenzepine Elanzepine Fluradoline Methyleneblue Monatepil Nuvenzepine Oxetorone Perlapine Pipazethate P7C3 Pinadoline Pirenzepine Pirolate Pitrazepin Pizotifen Profenamine Serazapine Siltenzepine Telenzepine Tipindole Tropatepine Zolenzepine Portal:Medicine 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