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CHEM 183 (143)
Lecture

mental illness 2.pdf

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Department
Chemistry
Course
CHEM 183
Professor
Joe Schwarcz
Semester
Fall

Description
Lecture9 October-30-12 1:08AM MENTALILLNESS 2/STREET DRUGS • Neurotransmitterssynthesizedinvesiclesandwillflowintosynapseandfitintotherightreceptors Neurotransmitters: • Reserpinecausesnorepinephrinetoleakoutofvesicles • Amphetaminessqueezenorepinephrineanddopamineoutofvesicles,enhancingactivity • Tricyclicspreventthereuptakeofneurotransmitters • MAOinhibitorspreventthebreakdownofneurotransmitters • Neurolepticsblockreceptorsfordopamine Schizophrenia • "lossofcontactwithreality" • Visualandauditoryhallucinations • Delusionsofpersecution • HenriLaborit(1902) foundthat patientshadheartattacks priorto surgery ○ Thoughtitwasdueto suddensecretionofhistamine ○ TriedanantihistaminePromethazine(phenergan) ○ Foundthatitworked ○ Investigatedcompoundsofmolecularsimilartopromethazineandcameupwithchlorpromazine(thorazine) -hascalmingeffects ○ Chlorpromazineworkedwellandsoitwasusedonschizophrenics ○ Highlyimpact ○ ButdevelopedParkinson-likesymptoms • NathanKline(USApsychiatrist)experimentedwithreserpinetotreatschizophrenics ○ SnakerootplantinIndiausedas an antihypertensive  Bloodpressurelowering  Alsonotedtranquilizingeffects ○ Lookedintoitandreserpinecalmeddownhisschizophrenicpatients ○ AlsoresultedinParkinson-likeeffect ○ Chlorpromazineblockeddopaminereceptors ○ Schizophreniaischaracterizedbyhighamountsofdopamineinsynapses ○ Reserpinecauseddopaminetoleakoutofvesiclesbeforegoingtosynapse • Schizophrenia-toomuchdopamineinsynapse • Perphenazine-treatmentforschizophrenia • Haldol • Allbasedonchlorpromazineandblockdopaminereceptors • Drugsusedtodaymodelledonchlorpromazine ○ Clozapine(clozaril) ○ Risperidon(risperdal) ○ Olanzapine(zyprexa) • Eventually25%ofschizophrenicsachieveremissionwithappropriatemedications • Sideeffects:Parkinson-likesymptoms • Newerdrugsvs.olderdrugs • Olderdrugsworkjustasfine • Newerdrugsaremore$$$ • Notclearifnewerdrugsarebetterthan olderones Depression • Morefrequentlyencounteredthanschizophrenia • Morefrequentlyencounteredthanschizophrenia • Feelingofhopelessness,pessimism,uselessnessfornoreason(notriggeringevent) • Antidepressants: ○ Tricyclics-3rings ○ Firstantidepressantresultedfromasearchforan "improved"versionofchlorpromazinetotreatschizophrenia ○ Imipraminewastriedtomimicchlorpromazine  Uselessfortreatingschizophrenia  Goodfortreatingdepression ○ Imipramine(Tofranil)blockedreuptakeofserotoninandnorepinephrine ○ Quicklyfollowedbystructuralanalogs ○ Deprex ○ Sideeffects:  "anticholinergic"-drymouth,blurredvision  Whattricyclicscan dobecausetheycan blockacetylcholine  "antiadrenergic"-irregularheartbeats □ Blocksadrenalinreceptorsite ○ Howto increaseserotoninandnorepinephrineinsynapsewithoutthesideeffectsofthetricyclics? ○ CameupwithProzac(fluoxetine)  Anti-depressantdrugbasedonmolecularstructure  Didnotblockadrenalinoracetylcholinesites  Selectiveserotoninreuptakeinhibitors(SSRIs) ○ HowdoesProzacwork?  Transmittingcell,thatreleasesneurotransmitter,floodsthesynapseandactivatesreceptorsinreceivingcell  Afteritdisengagesfromthosereceptorsandistakenbackbytransmittingcelltoberecycledandusedagain  SSRIsblockuptake,meaningthatyouhavehigherconcentrationofserotonininsynapsewhichhasanti-depressanteffect • SSRI(Prozac)SideEffects: ○ Nausea ○ Anxiety ○ Sleepdisturbances ○ Sexualdysfunction • JosephWesbeckerworkerinLouisvillemurderpeople • VictimsclaimedthatProzacmadehimdoit • ResearchitProzacgavesuicidalthoughts • IncontrolledtrialstherewasnodifferenceinthefrequencyofsuicidalthoughtsinsubjectstakingProzac,atricyclicora placebo • Scientologistsnotconvinced,wantpsychologicaldrugsoffthemarket • TomCruise OCD:Obsessive-CompulsiveDisorder • 2%of thepopulation • Chemistrystudentthatwasscaredtodolaundrybecausehewasafraidthat hemightget hiscats lockedin ○ Asmart guywhoknewthiswasn'tpossible ○ Wasverydisturbedbyit • Somepeoplefeelthattheydidn'tlocktheirdoorswhentheyremembertheydid ○ Needtogoback and check--can happenas much as 350 times • About20%of firstdegreerelativesofpeoplewithOCDhavethedisease • About20%of OCDpatienthaveTICSand 50% of patientswithTourette'ssyndromehaveOCD ○ Tourette'sSyndrome-tomakesoundsorengagedinwildmovement(mostlymakingthesounds) • Obsession: ○ Unwanted,unreasonable,intrusivethoughts ○ Contaminationconcerns,harmtoselforothers,symmetryconcerns,savingconcerns,"perfection"concerns • Compulsions: ○ Ritualsperformstogainrelieffromobsessivethoughts • Howard Hughes(engineer)soconcernedaboutcleanlinessthatheneverwentoutofhishouse • Perfection-tryingtolineuppencilondesk,getupsetwhenitwasn'tordered • BirdscanhaveOCD(peckon feathers),dogswillchewonlimbs • OCDisnot dueto somedeeplyrootedemotionalconflict • Sowhatcausesit? • Somethingiswrongwithbrain • Injurytothehead,epilepticseizures,strokes,cantriggerOCD • PeoplewhosufferedstrokescangetGourmandSyndrome(suddenlythinksaboutfoodallday) • Whenbrainisscanned,therearedifferences • PetscansofOCDpatientsshowthesamereductionsinbraincaudatenucleusactivity(centerofbrain)thatoccurfollowingsuccessfuldrugtreatmentarealso producedbysuccessfulbehaviourtherapy • InfectionscancauseOCD • PediatricAutoimmuneNeuropsychiatricDisordersAssociatedwithStreptococcus(PANDA) ○ ChildrenwhohavehadbacterialinfectionsmaydevelopOCDlikesymptoms ○ Bodyreactsto infectionandformantibodies ○ SomehowantibodiescantriggerthesesymptomsofOCDinbrain ○ CanfilteroutantibodiesfrombloodandcureOCD ○ Antibioticsmaywork • OnaveragepatientswithOCDsee3-4doctors andspend9 yearsseekingtreatmentbeforecorrectdiagnosis • Onaverageittake17 yearsfrom onsettoappropriatetreatment Diagnosis: • Doyouhaverepetitivethoughtsthatmakeyouanxiousandthatyoucannotget ridof nomatterhowhard youtry? • Doyoukeepthingsextremelycleanorwashyourhandsfrequently? • Doyoucheck thingstoexcess? • OCDisaddiction Drugtherapy: • AnafranilgivenfordepressionbutimproveOCDsymptoms ○ Increasesserotonin ○ Sideeffects:dizziness,sedation,drymouth,weightgain,sexualdysfunction • Todayrecommendedtreatment:SSRIs • Prozacworks thebest~40-60% respondtoSSRIswithan improvementinsymptomsofsome30% • Atleast10-12 weeksarerequired • Asmanyas 90% relapseifdrugsarestopped • WillhaveOCDallyourlife • SSRIs: • St. John'sWort- mildantidepressant • Behaviourtherapy ○ Forceyourselftoengageinactivitiesyoudon'twanttoengagein ○ 10-20 sessionscanimprovesymptomsby85% ○ Confrontationtherapy ○ Newestapproach:transcranialmagneticstimulation MonoamineoxidaseInhibitors(MAOInhibitors) • Researchrelatedtotuberculosis • Iproniazidwasdrugusedin 1950s to treat tuberculosis • Hadsideeffect:causedpatientstobecheery • NathanKlinetriediproniazidondepressedpatients • Itworked,butsomepatientsdevelopedhighbloodpressureandstrokes ○ Thishappenedbecausetheyatesomefoodsthatinteractedwiththemedicine • MAOregulatesnorepinephrine,dopamine,andserotoninbybreakingthemdowninthesynapse ○ Belongtofamilyofmonoamines • IfyoublockthemwithMAO inhibitor,haveanti-depressanteffect • Certainfoods,likeagedcheese,containtyraminewhichisnormallymetabolisedbyMAO • Buttyramineisavasopressor(canincreasebloodpressure) • Ifyouare takingMAOIand eatfoodswithtyramine-->willleadtohypertension • PatientsonMAOIhavetostay awayfrom: ○ Beer,wine,chocolate,chickenliver,herring,agedcheese,andcertaindrugslikeDemerolanddecongestants • NowMAOInotusedoftenbecauseSSRIsandtricyclicsworkbetter BipolarDisease(Manicdepressive) • Alternatebetweenhappyanddepressed • Inmanicstate,peoplewillgoonshoppingsprees,sexualpromiscuous • Willalternatewithdepression,thencycleback • JohnCade(physician)wasinJapanesecampinWWI • Notedthatmaybementalillnessiscausedbysometoxinthatentersthebrainandissubsequentlyexcretedintheurine • Afterwar,injectedurinefrommentallyillpatientsintoguineapigs • Urinefrommanicpatientskillguineapigsmorequickly • Thoughturinefrommanicpatientshadmoreuricacid • Triedtomakesolublesaltofuricacidand madelithiumcarbonate and injectedintoanimals ○ Foundthatithad dramaticcalmingeffect ○ MadeitintopharmaceuticalmarketasLithiumCarbonate ○ Worksbyinterfereswithinositolsynthesis  Inositolischemicalmadeinnervecellafterbeingstimulatedbyneurotransmitter  Triggerselectricalmessagesentdowntoneuron  Sideeffects:tremblinghands,nausea • Differentmanicdepressivedrugs • Doesn'tcuremanicdepression Anti-anxietyAgents • Treatmentofanxiety • Anxietyisafeelingofapprehension,uncertaintyorfearthatisoutof proportiontoastimulus • Firstdrugusedfortreatingwasbarbiturates(butisol) • Butbarbiturateswereaddictive • FrankBergertesteddrugsforantibioticactivity ○ Experimentedwithmephenesinanddiscoveredthatitwasamusclerelaxant ○ Whenusedinanimalsitreducedanxiety ○ Usedinpeopleanddidhaveanti-anxietyeffect ○ Researchdoneandnewmolecularsimilardrugsreleased,likeMeprobamate(Miltown) • LibriumbetterthanMiltown,calmedpeopledownandallowedthemtosleepbetter • QuicklyfollowedbyValium • LibriumandValiumincreasesactivityofGABA ○ Inhibitoryneurotransmitter • Notideal • Widelypr
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