Afchen Westi

Ardpychoaic Drugs: Clldcd rrd c€tr€dc Stndler 

Afchen Westi 

Ot sc) 

It.p$hctrt of Blocbenbtry 

UrtvcnLy of l(rnchi 

K|rrc -PrUrtrl 

20vl

Arlhrychotic lhug: Cllrlcd |trd Gctrctic Sbdler 

A lhcsis $tbmiafcd 10 tho Frculty ofScicncc 

Univclsity of Kanlhi for tc D4rce 

of Dolcor of Philo.ophy. 

by 

Afihrn W.rd 

(M&) 

D{|rt!c!t of Ehchcr&try 

Udvef!|.y ofxrrrcbl 

K|r|cnLhkb.|r. 

2WI

This thesis is dedicatcd to my loving daugnrer 

Dur-c-Fatima (Fifi), my par€nts & all my family members 

with lots of lovc for all of them.

CONTENTS 

Acltrowledgeo.nb ry 

Lbi of Abbr€vhrloB 

Lirt ofFiguG vrrlx 

LiltofTrbla x 

Ab*rNt(Erglkbrudu) XI-XVn 

l, ltrtrodn(tl0o I 

tJ R.vioof|-it.nrur. j 

1,2.1 Schi&pnrcnir: Syhproms. PANSS d

2.4.4 Ccl El*tophoeisofPcR Poduct! 30 

2.5 Taq I Dig6tion ol PCR Podlcls by Resuiction Frasment Lcngrh 

Porlmorphism (RFLP s) 

2.5 | C.l DletronhDicsis ot Digc$tcd t)NA 

2.5.3 Statistical analysis 

2.5,l.lchjr t6ring uin8 . x c @ in8ocy t$16 

2.6 DNA S.qlacir8 ofrh. Amplin.d prcdkt 

2.7.1 Expdindr.t Anima& 

2.8.2 Collelion of smpls 

2.9. I D.rminrion of loLt potci$ by BCA Kit M€rho

2 I3.6 Estitution ofAbsoture lndicd 

2.13.7.1 Dctcminarion of tron 

2.13.?.2 Detcmrination ofTolot tron Binding Capa.ny OrBC) 

2.13.?.3 DcrhiDllioo oaSetuo FcBitin by ELISA 

2.14.7.4 Pmc rsc Ttusactrin Sdudtiotr (o/eTS) 

Ll AdiPs tholic drugs, side effec$ dd PANSS 

3.2 DRD2 gene pollnoDhism in SchizophFnk patior! 

3.2.I sequoc. amtlsis of the 3lobp dpun.d ptudud of 

DRD2 gd.. 

3.3 AntiFstrhoric Dru8s dd Rcgionlt Brajn Neu,oransmirrcB 

I4 Dtipsychotio Drlgs d l,blcir hl[tc 

3,4.2 Pblcin cohpon.n|! 

1.5 AnlipsFhotic dtugs ard HeDarologiql DJeruis 

4.I Anripsychotic dtug lrearm.li, PANSS, EpS ed pol)moDn6m. I I o 

4.2 ArlipsFnoft dng helt'idq EpS ed DRDz em. polrDorprln llj 

4.3 Naor.nlmitld ed edFrychoric drugs_ 

4.4 Hem.robgic.l dls6i4 !d eti!.ychoric drugs t2o 

4,4.1 lon Dcficicncy Anmiaand tlpical.nliFr.horic rearnem t20 

4.4.2 Neutrophil clrotoxicny, protcnr pronte ed arpi.ul onlipsyctDlic 

48 

48 

48 

52 

51 

65 

85 

35 

,0 

t22 

I25 

t21 

r-v l

ACKNOWLEDCEMINTS 

I m than*fu, 1o almiehly AUah, mosl hunbly aor lFling enablcd mc ro conplere rhis 

My simGl $eks ed gFtitude to thc dccllot dd sustair€d suRcillee povided by 

P@C Dr Nikhat Ahncd Siddiqui, D@.dndr olBi@hcmistry, Univdily of Ka@ti. 

*hiclr cnablDd trE ro cofrplctc t|t rc$ .[ s.rl lh. brilli]N rturliry ol scicnrilic 

lhirrking dd lhc conlinnous suppod of 'ny $'pcrier fc rhc comcBl.ncs il rhc 

M, lhinks rc rho duo ro lhc Chliecmo|]! ftot Dr. D0litsh{tr Jrbccr ll!le[. ill 

rqchi'rsnnd lon-tqchins srar of Dclalncnt ollliochctuisky, Uri!.sily olKuruchi 

I sish ro qpr$ toy dn s 1o Pmt Di Ri& Ahmql Hlshnri. v'cc Chrtrccllor, Jinrlh 

Univcuily lor WonEn, and.ll a&ulty nr hc6, lor ftcn suppod. 

I would b. failinS in my dury if I do nol exlend my henicsl thdts aor rhc 

cncouagmcnti and help ofDr. Mcndi A. M4ji, Pathologidl kboraroncs. TnMk are 

duelo Pnt Dr. AnwdAli Siddiqui. Asociarc Dean Reseeb, rheAga Knrn Univesity 

ed Hospital lor pbviding ame f&ilily dunng the cou6e of my endsvoB ro codplete 

I wodd like ro thdls Ms. Hila Rie od Dr. Ri.z Ahned, Di@lor, tnsritute of Ctinical 

Ptlchology &! pbvidine snpl6. 

SpdialwordsoIrh lsaod sntiludctoDrt tricnds, Dr. RubimChnDi. Dr. Asili'Ahnrqt, 

Ms. Snrn D Mushtq, Mr. i4ulnq{ Nntvi, M5. Sudi, i4l d lrl Ms. ttizM Kh , tor 

lheir Lind dd coBbl€nt noral $pport dtd encomsmal in nuF.oos mcnonbt€ 

My sinccrc Egdds for my pamti, nei mDAo md papa, whosc piarB, lovc and 

glidfl.e hs hclpad me sail thmugh dinicuh ch.pi6 ofny life. My fath.r rhd morhei 

have beo ulln-sutponive, md this thesi! is dcvotsd lo their €flons and sfiific€s. The 

olBhdi.a .oop@lion of ny bbrn.E, !i!ro$ and .ll hy fm y m.nbcs, lhcir lolc 

ed conlribuiion in poviding ga@G ed sur.in.d suppon n.d. rhir work possible. 

Corbpldiod of ny delorrr. rh6n ir Fr erh.r lribut. 10 ny gmdpc.r vno wqe not 

rh.m*lvd rdy cdE.Ld bur g.hinS nisha.duqrion b .h. gomrion ro aoltov wc 

rh.ir mi$ion. M.y God 6 rh.ir suls in dd.l p.e.. 

Hov could I i.v. arlve..d 6fiha wirhout utuhsl€bl€ €o.ndflcc of mv tife o{lnd 

Mr. Zeahd AIn.d Wsri. for po\drg ps..ful afr€.riod. .h6ph.rc ;Fund m.. a 

! cut ofwhich rhc pGcnt sludy ha b€en consummalcd 

NoN I vish !o cxpre$ dy heonid bve to ny daushler DuE-c-Forima itifi). I am 

cxtmely cone'ous abour rhe @niorl ofny littlc baby dunns nry srudi6, n is very 

difficut lo neagcj bul ny daughler prev6 h.Eelf a pMioN gin of cOD for mc. 

This slldy wa litrdcially soppon€d pdi.lly by Palish S.imcc Folndarion Cnnr 

PSF/RE9BImECH/S-KU/MED (42) ed Univc6iry olKm€hi.

FoUo$ t!3 .r. tt. Puhl.rrrodPr.sr.d... r p.n ol ln. ltstt: 

Pci.r pr€.6l.rlo! / Published in Mol6uld ed Cclluld Por€onics Absrracrt 

i$ue for IIUPO 6r' Amual World Congrc$, Prcl@nic.: Fron Tehnology 

Dcvelopm€nr ro Biom.rkdApplicalions". S€ouUKore. 2007. PlgG409. 

R4ipi.!r ofYoui Scldtilr Aw.rd. 

Slbmincd for Publiotion 

Mol.o|!r Psychi.lry,2lx', Au€lic dbrribllion of DRD2 Ccnc potynophism in 

P.k6rani $hiapnrcnic patiqls. 

Submdted for publicotion 

abod-2007, Anlipsychotic drugs d trctr dcficiency rtrcnlij i,1 schizolrhrcnic 

Joumit of P.tisr!! Msdiql A$airrto! 2006,..Ctoaph tnduc{t Ncutroltril 

C}lotoxicity in rak" 56(2): 62-s. 

Prkistar Joun.l ol Medic.t Sci.nc$ 2004 -HalopendolIndlced Veiations in 

En.lologicalhdics". t0(3): 19?-200. 

P.per Pc.!t rlod Publisbcd r! lh. proc€edrnss ot 8'i Biemiat NaloMl 

ConlelEM ot PSBMB on Em6pn8 Tmds D Bichmffy ed Mokcute 

Biologj,, Krrrchi-Prtist.n, 2005, p 4!, 

lucltlcnlof Yo ttsclunlstAwrnl 

P$l.r pBeot tlou/ Published in lh. 

Synposium: ccnorric nnd pmtoijics iI 

Prcc€edin8s of l8D FAOBMB 

lMllh rDd nSricultrrc. l,.norF 

P.per pGdhdon/ Pubhshed in $c proc.ediner of 7r hrhrUond Con tercncc 

ot PISBMB, Trcnds m Siochmistry and Morecutd BroroSy. Lrhorp.kbrrn. 

PGt . Pr*!hrlo!./ Pubtish€d In rh. peedrngs of ?r EuBia Codadce of 

Chmical Scift€, K.rrbtprt|thtr. 2002. 0140. 

PGr.r PEqtrrlon/ Pubtisned rn lh€ prcceedrnsj of t6'i FAOBMB 

sFpos'um Fom Cnc b Pmtein : Fdnries in BDch.nrkry.dd Votecuh, 

Biolo[y. Acrdcmtr Shicr-Txipcichtnr. 2002. o ltS. 

R4lpi€!t of younr Scl.nrist A"rd,

ctz 

DOPAC 

DRD2 

EDTA 

EPS 

LIST OF AEBREYIATIONS 

5.HiAA 

tHydoxy indol&etic &id 

s-Hldrcxr1''?rlnirc (Smronin) 

HPta ''HT ECD Hrsn Pdfdmocc Lrquid Chmmbar.phy-Eler@h.miclt DeE@r 

MCIT 

MCHC 

MCv 

MgCl2 

NS 

PANSS 

PCV 

PS 

TBE 

TIBC 

Tris 

TS% 

UD/D 

wBc 

Dihydor}?hm/eclicacid mid 

Elhylcnc Diminc Tclru-edalc 

Ext6 Prmidd Syidrcn6 

M€d Corpwnld Hdoglobin 

M.d Cell Eemoglobin Conc.ntration 

Mcon Corpo*ulrr Volutrrc 

Posilivc and Ncsnlivc SyndbnE Scorc 

Polyhe|e Chain R@tiotr 

Rsd Cell Dhrribulion Width 

Rqtriction ftagmcnt lcngthpollmorphis 

sDS-PACE SodrM Dcdd yt Suttal. -PotyacdMde Cet Et4rEphorers 

TrG Borare Elhylde Dihin. Telra A@ri. Acid 

Tot l lron Birding Clp&ity 

Ttu Oldrcxy mctlyl) mino methdc 

% Ttuufmin Salu.tion. 

Undig6rql / disBtcd rcR producrs

figure3 

nigun5 

(h) 

FlSur.l! 

(b) 

ngu..l! 

G) 

Flgurc 13 

(d) 

Ltst oFFtcuR0s 

Magn6ium (M8Clt gadicir (2.5 - L2 nM) hr otrinizins 

PcRcondition, 2E 

Temp€nore gradienl (52-62'C) foroptimizinB pCR condirion 29 

Calibration cw€ for NelbrtusDtuw. j8 

Sldd..d c!tuc to. Tr}?bptun. 

Abefptron spetnofKyncurcninc (250 500nh). 4l 

Slandard curvuofrlcnroSlobin 4( 

clenosmd leaiion ofDRD2 saa 

Slruclurc oa 3lobp re8ion ollhc DRD2 gcoc spdnins rhe Taq I A sirc. jt 

2%.gdosegelofrhePCRpEducrmplifying3tObpofDRD2gcnc. 60 

RILP'S ofDRD2 E€ptor g.n. on 2.5% sg&e gct. 

Th. diftmral pdh of undia*r.d /dis6lcd (UD/D) win 

Trq I EftlonuclN PCR/RrtP5poJulIoh:5 e r$tus,gt.t n-) 

Thc diffcrcntial pau€m ofundisered /disesred (UD/D) wirl 

Taq I Bndonuclcdc PCR/RtjLPs D&luct on 2.52, rgrroscgct. d:! 

Mudon In lh€ nu.toridc Ecqucnce otthc DRD2 gcne hrqng 

rrqr A s{c. 

Sequcncc rclulk of rtObp anrnt'ficd pmJcr otDRD2 Nnc of 

Schr&phGnr pariab iolowrn8 chonk rcJlmenr ot iatop€riool 0- 

Sequdc. r*ull5ofttobp Mtlti.d pDducl otORD2 ctre of 

schizophroic par6c ronosi.schrcnic n hor of;top€ndot. 68 

BLAST 2 S€9u@c6 R6ulr! of 3 I Obp mpUfid prcducl ot DRD2 

geneor*hihphmn paE r fo|otrrnschrcnr rFahdr ol 

naopcnoot, h, 

TmeqMce R6ults of 3l Obp .mplitied poduct of DRD2 goe ol 

patenrs aolloqins chrenic tl€tnal ofhabEndot. 

j8

(b) 

(d) 

rig(rc t5 

(!) 

(b) 

o) 

Figuru 19 

Scquen c cuX.of llObp lmptrfi cd poducl of Dl(D2 rdc ot 

p.t..nls rolloqinC chFn( k.rmenl of hJoperidot. 

S€qumr 6utrs of I I obp hptified pmducl ot DRD2 cene or 

>cDzopMd'c pabqls fotlohnS chrenr tMrnql of halopddol 

BL-AST 2 Slqutues hatysis ofJlObp nplfi.d pod,.t or DRD2 

Smed shr@phm( patcd! fo o*rn8 (hrcnic re.tmenrof 

j T"S.r"n* .,ar"" or r toUp @pl cd prlducr or DRDI ede of 

rcnrbpr'rdlc pabnrt fouowingchmtoc hm6r othrop€ndot. 

Jqucn( r$ulll ut I txht r,,ptrliot fru,tL dlt)t{D,2 L(tr1ur 

scnraphrcnic palienrj ro o*ingchonrc l@rncnr o r Cto,.p, nu 

Scquq.! @utlsofJr0t p lmplficd poducr ofDRD2 Kncot. 

rch'4phMic paridts fo o$,ng chonrc r@hcnt of Clozpinc. 

BLAST 2S.9ud.6 o.ttstr ofl lObp mphfi.d p,oducr ol DRD2 

sene o' *nrhphmn pau.nb foltowine(hronrc r;,lmed ol 

TEG.qucnc. adys6 oa J I Obp npt, tied prcducr of DR DI gcne of 

rnrzophnrc p.rists to o$ inA chrcr. @ondr of ctozrpin.. 

?iltllloi.oldoeTtD. @ intsariq,n d,rrcrcnr rer bE,n rsrcn6 

rorowhg.hmnj\ Olsn*tu veda],sr yM,rcarmenrorha,op.adol 

Cmpai$n of dopamc @rccnkauon In rtr Shdrum ,o o*,ng 

mrcdc (2r @ns4tir€daF, VM rF,rmsr ofhatolmdot md 

c,ozaprne. 

.onplrilon otrHTrcmolrdion In d,ffcrc ri b,rir1rcc,urs 

,orrc*hl drEr. (2r, ms*dncdrlsr t/M rrc.r crr "t t;bt,..r.,,,,,1 

|^-mpeibn otd tnin and tjve( Tryprophrn 0rg/s $et wcie ol 

nslo loltowingchrcflc (2t coro*"r,,. aay"i trV rr*r.en o 

uopendoi.nd ctozapine. 

Iqty Gc/g/hr) toUo*ine (@nrc 

(z | @GeuNr days) yM termcd ot hatopcndot. 

78 

3l 

8l 

84 

12 

7l 

15 

71 

30 

88

Figlr.24 

l.lttrrc25 

Fi8urc27 

RJr liv!' TrrTbnh p)"ot,bc.,crn r) r,,d d n r ro o*tr,! t h,ur,. 

lzr cons(u(rvc d,,sl uM rcJ[ncnr otctozJpLne 

Prcl@meealysis ofahdpsrhoric dtus rroaled serum sadptes. 

Compmbn ot_Hhabtog(dt rnd,ces rr hdtoperidot MJ c.u,,p, nc 

tr4red $hiephHic panqG. 

Cômpmn o, HtutoS,cdjndic6 in Dts to owngchFnrc 

r/ r - consuuvc days) yM t@unar of hatopndot d

TrbL 3 

Ltsl 0F,rAar,Ds 

Dcnog.aphic and cliniclt fclturcs ot6chizophEtric paricms rrcdcd 

enh hllop€idot ddclozdpinc, 5l 

Cmld'on bcrwen PANSS drt ort,q clin,cJt pJ.r,crcNot rhc 

*rapn|m. pal'.nls reled with hdtoPaidot ed ctoaD,n€ 54 

Anlipslrhotic drugs &d side .tlcrs polt t€ eiated *ilh lt?|ql 

&d art?rc.t dripsrrholic dtu85. )) 

Dislritub@ chmrsislics of PANSS ncns ure{i tor (he diagnoss 

orschrzothrcnicfiticnlsucrlotsithhrtopcridotrnd(to/Jpru 5,, 

Disn rbLrion of DRD2 gsolr?c and rct edpdaherers ro Tdq tA 

porlmorpharn rn rhc hatoncr ot, ctoanincJnd(onfot,LDJq6. na 

ltr?lothdn Pynols! rclîlylrr8 !A,j rtr tul jrvcr tir,tos,ig cnnr,c 

nrnrstrdtDnothrtotlcriJutln tulr 8r, 

Tryploplltatr- PIrcLsc &lrvity {rrg!,rr) In nl Lvq to ovin8 cnFnrc 

.ffrrsr.lon ot cloripin. h rr1l. 37 

Compdbnofrod *M pFch @rcqFalion nEG fo owhs 

cmdr ddmhisFarion of hatoD.ridol &d ctoaprne. e I 

Clmpesor orEts.M por.h @nponmk ob*dd on SDs-pAGE 

rns oe cmn'. adn,nisrarion of hdoperidol. ,J 

aômpriso olar rtuh poGm conpontr6 ob*1d or Sls-pACf 

rncr ric (rturL.'dnrirlnrr.iinl ct(.i/,,,..trJ 

Cilculalioc use{t for inlerprctinS .ryrhrcrle indice in oider D 

oEcnflnare two lt?6 ot m,crccyrc ancmd rtrJtsrni, n,nor rrd 

Au€Eti@s in hmrotoSjcat p.mcr.G ofmls aR6 chronic adninisr.rion 

Altcnrroc In lton prcUt€ of ra6 .Rcr $. chmnic admrnrsbauon or 

naop€ndot Md ctozpine. 

Cohpdis!0 of @kl &d d, r.Fnuat WBC cobl in scluoDtu enK 

pansr. ronoqng chmnic tE:rd.nr of hstop€ndot dd cioapin.. 

105 

t08

ABSTRACT

ABSTRACT 

Thc pccnr wo* d6rib6 thc sidc c'r€t pbfilc dnd rtjc purrrjvc h0ucncc or scndrc 

&clo6 in cpo* ro rh. chftnic etipsy.horic dns lah.nr - i coh6ron rhfrpy in 

trdm€nt of *hizophr€ni., Hatop€ridol lnd ctoapinc arc rhe nosl comnonl, uscd 

lntipsychorio dtuss in thc Fychi.ric itrns*s in p,kistah, wnich havc. pr€valcncc uc 

of abotrt 10-160/0 in thc adnlr poputarion (Cadit 2007) Haropsidot, a rmic 

dliFFhoric dtus, my lcad ro app@cc of drn prlmidat srnpbns (EpS) in 

6pome b rhe chonic keatnent, rsulting in eovcmenr di@rd.u, Clozapinc, an 

altlral dtiplycholic dn& induc6 fwd EpS sed in ircmar Grrtat schizoptmic 

Thc phannacogcndjcs of schizodrcni( ponicrlnrty thc bh of gcnclic nrcto$ ir 

delmining srnproh responr ad sidc cff@b of dtipsycnomc !rcah€nl h6 bccone 

Frrind iD tne E@r yqs. As@iarjoB with ctinicat ourcom6 havc bco tound fo, a 

vrricly ofcoDmon func(omt polynoFhisms in c,niji{ilrc gcn6. .t.hc cnrftGis of thi3 

Bcarch w6 on the dopmj.e @crlor ecic (DRD2), spccitically. Thc polqtial gcnclic 

prcdicbc of $h'aphmir atut $nc idcntificd scnqlE ass'alons wrft neg{iv€, 

deprssive ed .osnitiv€ synploDs w@ !l$ inv€sligat.d. R€spon* of p.rints lo drus 

ftalne a w.ll a the lidc .ffer profitc such as henalologjcal drsEid, weiBhl 8!in 

ed netalolic syrdrcD. fouoeing q?icat &d arDicat dupsrlhoti* r,qunoq is ate 

Studi€s w€rc conducred on borh nls ed *hiepn enic parrents. Sp6guc-Dawle, rats 

@eived a d.jly irlrdu$ul[ irjodon wirl hatopendot (0.2mSlK, or €tor4ine 

(204/'Iq) ftc doubt€ @np&i$n s4 D.dc in ordd to voty rhe obsctued BUI$ by 

sins botn cohm€rcially av.ilabte (Sed.r' Novdis) and punried fom (Sism!) ofthcso 

druss. Thc bl@d lamptcs wcrc coltelcd aDm lhc schizopnrctrrc prucoIs wtro wcrc otr 

cnbmc lrehor wi& hatop.ridol or cro2.pin. for rorc tl|e r z w@ts. 

Pdrn6cChain Rqcrion R6kicrion thsnEnr tcnslh potrnoq i i (pcR-Rrrr,r.s) 

usod lo l)Tc thc DRD2 scno ir sctibplrrnio prti.ols or, un,onrc nnrlxlchorrc drug 

trcalment. Thd dilterenr DRD2 gene altclic panms wcE obs€p€d b! eallzinA rhe 

RFLP'S prDducrs on a€re. ects, dcisnal.n 6 At (3lO bp), a2 {r8O & l2o bp) lnd

AlAz (110,180 & t20 bp). A Ddked incrcdc io thc frcqucncy of Al a etc ot llrc 

DRD2 gcnc w6 obswcd in both halopcddot {d cDaprne rcdqd *hreDhrcnic 

paLiqrs ln=l2o) @mplrd ro rh€ iomal @nlrots (n-44) No drfi@c. ws obsdcd in 

or. rll.& n quocy wirhi. rh. trqrmdt Srup3 itslt 

A nov€l od polendaly iEpondt findjn8 of$e prcsenr ltudy w6 rhc idcnrificarion ofa 

G to T iurllion in DRD2 g6e ar posiljo! 3282?bp dchjned by mc DNA sequ.rcin8. 

DNA s€quac. rut'.i. oftl|. 3tobp 

'!8nmr 6?mi.g rn potynorphic Ta{ I A sitc of 

lhe DRD2 Scnc ahowcd thar all *hizopl@jc p.licnrs, cnrcnrcany kated wirh 

halopdidol or ctozapinc, w@ hdozygo$ for a c to T lm,lion jn rh€ bss pan 

pctr'on 32827 a$ing. Scr36lc nuErion. k is inDondr ro notc rhal rhis C ro T 

munnon ,s ror 6$ciar.d wirh the non.*hizophrcnic conror goup, MoEovei lhc 

nutllion showed no signifcanr eret ,s $sessod by ecnc 

This srtrdy at$ ancnptcd ro qpticat. lhc djtTercnriit amnny ot hrtoldidot nnd 

c'oapnc on ncurolrnnsnriucr recpbn irducilg ! tuc cnuscs D hcu@hctrricrl 

p@file udcdlhg ttE rhe8peuric etfet! of.ntpsrhotic druC ,n $hroDltrcnia. 

I lErlicul&ly focus€{t on conenhdotu ofdopminc dd $olonin i, diffcrc Esions 

of €t bBio by Eins HPLC-ECD &.lysis (rlu€ !o ,on-.valabilny of hqd bEin 

s3hpls). Thc regional ar.lrsis oflhe dopmine dd serobtun neurorresni ds is 

ihol8ht to bc inportanr, s ory pbvide spejltc sit€ for lhc a.tion ofa.tpsrthotjc ddts 

dcPo,l'ng on rhc pccmc ot Oc difcrcnr ncu@hmsnx cr qcprna lku ,. tZ , 

DRD2. 

Signili@l .iIaG w€re obsFed io thc oncenration of.cuolresm,fc$ in diffcrcnr 

F8'oro of bah in 6!on* ro rhc chDnic rrormd or bolh hatopeidot dd 

cloapinq Thc .hmnic kqrrnsl of halop.ndol incesd h. @nc.nrration of 

.rlracelluld dopdine in aI rcgions (hrporhatmus, cortq eo snaon) excepl in Ur 

nid-bain. tr @ftsq ral,rdt witn .toz.pinc Ntlcd in m.,red der.& in all rhc 

Egioc d..pl h lh. rcnd in whi.h th. colmmj.Iy avaihbtc fom of croapinc 

show.d n{k.d inqes. in th. @,qFarion of dopdin . A sjgninc&l d.oEse w.! 

.lF foud in dopmine @nc.olrarion in Did bhin in both rhl @mcrciauy availablc 

&d pui6€d fom of ct%pir. lEa[n6r. 

x

Thc lryel of$btonin, dothd n.uoldsmnlcr ws signific.ndy inc@red in midbnin, 

btlothalmus ad sdatum followinB chonic ftarment oa halop$idol in borh 

.xl.nm.nLl abup. s @hpe lo @.Fol d.; hw€vcr, ..ltl[ detle *& obserycd 

in .odcx. In csc ofcloapinc co.curcnl d*.cr6c w* obssql h Jll N:giotu cxcNDr 

con.x *her€ fi. concenlralion of hlonin w6 jnccasd Es!.criv.ly jn bolh rb. 

qpmmot grcups. Th€ varying .ffd of lh.!. dtuss on ncubrrdsnil|c! cohcoralion 

m.y acmunt lor rhc ditfcrcncc in ftcn sidc cr€l protilc in rcspotr$ ro chmnic 

Th. elhs repon d in rhis thesis niF concems aboul hemobloeicat sidc ellecN of 

urlpsychotic drugs, vhich lktDlgh int cqucD( mry slill pos I potcrlid naz!.d. 

Our 6ults sugAd nodloring ofdce wbich mishl be hclpfll in moaSchcnr of dru8 

.cljo. Tnis study iddrifi€s a pornlial rots of trlic.t anripsychoric (hatop€ridol) 

llcalm€ot m $c dev€lopmenl of iron delcicncy demia in schi&pk€nic Datidts ed in 

sihal Snldi6. Almd ?5% ots.hiaphMic paidrs on lonSrm halopeddol retrncnr 

sbowd >loelo hypochrodi. ed mickylic c.tL wn€o cohp&.! ro nom@hmmic- 

nomoc),ric cells ob*tred in ctozapin€ ftcatcd paticnt!. Iron deficiency acmia. tikc other 

m'cmytc dtc|rxa w6 confimol uins adjunctivc t6t slch 4 scrum icnirin (ur 

indicalor of non srorage) or iDn in lhis sludy. Non.lhel6s, ircn tev€l aflerd by rh€ lwo 

drugs lr?cs arc nol idoric.l and nay rcprcscnr $c advfsc c|Iccls ot ililg rcsronsc 

rcponcd fo. thc ll6t rinc in $hibphrcnic prticnc fom palirrani Doputdion. This 

infomarion could b€ ldlizcd !o rupport possibtc monilonng sthlegi€s to rcduce btood 

dyscrasid fton aiipsychotic drug tratnent in schizophrenic palienrj 

Arolhd si8lilicdl linding is 0rc clozapi!. indeen ndrophit .rloloxicjry &d s.vfrl 

olhq h€dalological changd h $hiephmid supported by $c dara in tne El modcl. For 

€xeplc, th@ d. ceruin pell.l! b€rween rb. nndinss in hun& md 6ls on tonsrm 

clozapinc lrcallncnt egarding ndtrophil c,lotoxicny. Neuhpbil c'loroxicny is 

ddoEtrated in ctl expsindtrl aimals lmled *nh puified or mftm@ill 

pEp&alio$ dd paricntr expoed ro cbapin.; 60 % of rh6. pa(enrs so on ro d€vero, 

oyroloxrcrly, suggclliDg lh.r rhcrc nrly bc ddiriomt irc105 itr rhc.tcvdtoDnrcfr ot. 

croap'n€ crloioxi.ny i. od. Al6ough in |ni! srudy r did rcr aLlempr ro idcnlity dirolty 

lh. @tiv€ mcElolil* of ctd.tjne, bur sr.86 of cytobxicny *ere ob$cd.

To SaiD tunhd iui8h1 inlo moldt& mohdism involvcd in cloapinc-induced 

cyr.lox'c'ry. I onprel rllc drug oDdifiqt $ruD polcir pn,titc iI ilLs ,tlis slrdy is 

inconclusivc, how€v.r, patiminary Butte indicale clozapinc ft*ed emptes (n=12) 

.hov ur roaulred dillcMtlally .xpr.$.d clozapinc nodincd 5B KD dd 184 KD 

Dol4cpiidc in Ftun compat d !o hatopqidol trste

4.lll 

Lt'LrltSiL chhnic rrcah€d !te!,, Anripsrhoric J&(}it,r', 

il-t a. o v/l -f -,{a- ) f | 

fi' t Ls.tltzophqni a l} + r/dt le!) j ge.rsiae erea 

gr!, Jl.fJP|9!,,^nriplrho tjc il, /4 O b L t + /4 1 o-1 6% r., ft E L &/l 

\r t - +1 y pi.at Nnips'rd\ob,Iy'zHalA€ddot c! Lrrcbapine /rHatopedjot d 

-dlr'rlrMov.ment die'd€6 F,-tzE,/ 4,{ Eps ,P,,,! to udrtraporymoDhism 

iPf $u&blt Benmaa{tt cognit € syn&onerNogarE, cr€D'siw - 

-!"'Nyptcat.'twi,c.r.t,I,r/-r.tt e,,.tt be- -t,t ot. t L !1 --p.€di.j{l. 

,(weight Gain)Prtrgr.Hemalotogtoat dyscrasiasrrside €ffoct Drotite 

O 6,1u ?-/L S$izophBnia iAnimat Modet _iJd,Jt {Merabotic SyndMce 

e8,Fr7(10.2^stxg1 Hatoperidor/ctozapine l2onstk', al i)nl_-{ 

4 doubta @nwnsbn 2- L L.ta{,P( 60_l I \ht amuscurar Inieciion) 

-W')Pt(-!'tntpsycnotc commedat avait bb a pudfied arn ,,&l,gt f 

,lctozaqino,tr'tator€ri1,ot t {.ltbL lLo;Ll./s(jleophteni. 1t 

{onOz Aane {"ttz-rrru Cnonic A jpsych.nc ttjt/, _Z+/Li!)agF 

{A€a,@ g.lz RFLps produe, r!/l)pt@ pcR-RFLps 2- Lc.no'pi^s 

Ai (3ro bp), lar?.ldArf€lic parbm -.PctL oRo2 gene JJiz-v-1.--av 

412.-v1)t5etet. -(v(!!. alA2 (3i0, 1Bo, t2o bp) ,,r a2 ,(180, 120 bp) 

dd)6l1 lltaeLDRo2 .toEat !.Le!,tctoapiê ,ttlatop.r*,ot 2 !t-/, 

J) Jlea Nbtb fitauanct oV" Lrwted saups "1t4L,),fJri_ _t )t tet 

xv 

-ttde-".e.

4-gc.n6 sequencins ta'li{uuawn et -11t-,.( f,tJx 

r-DNA s€qu€ncing AnalFis Z Taq iA 310 r€sion ZDRDz -+$!..t|,t 

lchrcnic iroatnsnlzCbapiD€,rHatopoddotr /-/Schi&phpnk, P 1t J tt rt! 

ser 36ll€€ rZZG-T TEnstbnl c1432a27 bp -LCHomozygous *z 

ttt"r- cdzt'- v',\)/J,ve-r r mins on .l?J4/el 4rk_tt r)vLnurlton 

-{\y'na i' f d /a6c'Lo t Luut'ranl "bL 

dmeential {NeuDransmift E( ctwpine ,t{atopendot L(lOJ} 

4tDopantn6, t /'t r) 

"..PL Lt, ( 

" 4, 1,d,' L ( - r- { tF4t L,/ot 6 / anany 

_ f - t/,./ i APLc-Eco r eh n qct/izseroionin 

H*arol€rc€lside L^^ 8ychotj. t?{.h(da6 tLf &)tFt l 

, u/zS. - q,Pl 2- Lr oxic$te LII& t-t't', +J"r: -vi- LtrLerEcE 

4-r'r4',4{-!\tt)1 .'/-+&n,i,(cLr,h,tt' .,tv€t',a,!u,l+ 

Tyri€l df .on d€fi cie.cy Anemia Lt, L n J-,t/ i it o tr' AE,, o ?-/ Schizoph'rtnia 

A-/schiapnrcnia 1t7E /" U74-, iJ".tu Jpet. 4, I tyhn|p.ychoti. 

mtocyi:/rlhypochDmic,!r-10%Gc!12lchbnt tleainenlzHabpeidd, 

nom@y'ic-nomochomic cerls L ! A /r toabd ctozapine rvlsr -2 I 7_1nn, 

adjuncriv€ (t llon def€crency aieamis t/fnidocyic anae nia. .i,_(,gvL 

e n,ctt. 4,-+t .t'l!t+,Itbn I L(-t lttgtt (t,4)trr*iJn bniinrpbsr 

&.{,!xutrsa,aopn nr idl+,furl dt k,itcJto1ralptLet,,l 

- n Mi'.J aauu e areas Ltt L' G * L Jt;4L -f ,au + e 

-r* f ,dulGesional Braanar An"ry.i')lrF,"lry Hur.*n.rneo ..r' 

i! { sib ot adion L e!,1 antipsvcrrorcd Jr.r/neuotrangmirer €c€proF-;F" 

-PLRat b.€in/ Lh,Lchanjc rearn€nlzHabpe,idot,tclJzapins _q L / 

chrcnic tHaloperidol -tlrf 4,,lve JlLNlrnotranshirt6G d1,,, 

lmd-brain ai'(Hyporh6 amus. cod6r E sriatumr L/,,j!,1r..!,,1Lv6ana.nl 

0'26 r' l, & * LttLL ctoapin Lt, L rt tt*ot tt,ut| ema c€lor.r doDamin€ 

fcommorciart avairabrs clo.. pthe &@tter 4_J1&i!,1fii)rcd,nex LP 

'{l! : v"' ;2 v g (rin".nn.oonddopamined*thatn€nt 

xvI

Dopamine Llmld bisin Z.expenlr|e tat gtoups ohLclwpine .UU4/ 

ri',Ce Lchrcntc r.€atmentJ Harope dor -J' dr,{,,t"on""n ao^ 

&Zssrotonini,Csrriatum, Hypotha smu3 & Mid-b6ln 4€xpenm.nr.t soup. 

ctozapino,fi !,Jt - LRaEt), y'-,'a J, dt'r{,s,J aco,n,/,trC 4,;v',Ltvc 

{seotonin uk.coisx z-ll! j" {o1O,l 95(3 4",6a^.ntat srcup.gLL 

dNeurcf ransmitteE d# Z Jv, r I E e!'t !)r -t' j vt :1, q.licnnc€nrrarjon 

-t4,vl$)rt sida aflect prctite LNeurcrans'|.l,itlgt,-t )tjitLr, L'n$ 

J &bt.fd dysqa.i.s - - 6l

,94.41Lw ffi Lt,aC ,L'irL(W, dutwUl 

li]f*,lr+Vf0a14ff,Zd,.{rlrriribr tre,&?rrn-.. 

scllsftr FladrE {tt lZ- L+.r'Hq'r*fi|. trtceb dp"+ 

('lu{oat lala.t2aaugitZ*rc nre1511p 6".n ,*,4y 

ltd,t4/wi/*t4--l, rrwtd* J..+{J)a-td'rft lart 

-zl 

xun

INTRODUCTION

I. INTRODUCTION 

'Ihc idertincafun ofpatcm in g€nc cxp€riotr darasers prceid€ rwo bcnctiE l) insighr 

itrlo g.n. polFophisn 2) ch@cltriatioi oa mutdpte Scnc cxprcsion pDfit6 in 

amphx biologicll prccc$B slch 6 palhotogictrl srars . AccordinSlo acounuy pbtitc 

rcpon by WtlO Emb Rcgion (ww.cmrc,who.intmrh/whd/couhl.vnntitcJ,AK.hhr). 

&out lGl6% Pslistani population lulrcB fen leioE rJ.6 ofmild !o modcrsre nenbl 

dr$rd.6j only l@/d oflh* pdi6r! @.ivc tr.atndt. ?r.vat6l ma|.t .lisrdeE d.: 

d@6rion (6%), $hi&pbmia (t.5%), Alzi.imcr,s diree (l%:) dtd.pitq),y (j 2%.) 

(Gadn a al., 2007). Th€ morl sio6 nuitcstatios of rhe 66trl died.6 e 

tuicidll l6dtui6, Clm y rhc mcnd dj5..G mrk d founh pcnion dons rne 

8lob.l budcn of dis*e. hwcv€r, by rhc ,sr 2O2O n t f@€d ro jumD ro s4ond 

po$lior b.caus. of ldv.ne $cial circumridcB ed €nvireMent t .!@ni4 (Cadn & 

Knalid 2002). 

Sclizophrcnia is one of rh€ mosl disbting dd €ootiona y dev$ldrns I n$*s (Movry 

.l al., 2001). lt is ch@Iqized by a numcous dislincliv€ dd p,cdicrubt. symptoms 

contlollc

ncbaisn of &li@ of&tipsrhoric drugs hs cult€d in vrioG h}lolhcFs Elrcd ro 

$c n€nlal dieadr the naiBlay of heatndt of schizophmi. dd oth6 psrrhotc 

di$rd6. Th€ difla@ in 0E .flilily lowdds D2 deptor providcs lhe b6is of 

cldsiEc*ion oIlh. dtiFJchotic druesinto lypical (habFndoD a atypical (cloapine) 

prcdeitrg diffmt ntroch€nioal 5d inctional alIsls. 

Thft is d ill{)@itra int 16l in ln. ph@a.nctics of $hiaphdia panicdsly tte 

nls of g€nclic fa.lo6 in dct€mining srlrpton Espo.e ed side efGct of @ripsychoric 

llsundt Tho pltfut srudy is t@ui.d d sd.ric in0u@.6 in cpoN io rhe 

dtipsycnotic dngs treabrent. A!&cialioN wi$ $6e clinical outconcs havc b*n 

fourd for a widy of @motr frbctioral polForyhjs i. candidat€ ccnca (Ha@ et 

al., 1999; IaoLawa .t al., 1993). Sone eert fldingd ii this conr.xt will bc dsribcd in 

this slion. Thc ctr|pb6is will tF on polcnriat Sderic predictos on some iddti(ed 

genetic dociations Mlh n.gative, delre$iv€ ed coilivc srmplom. Thcn Bponse to 

dtug Eeatndt 6 wel 6 lnen 3id. efet prcnlc auct rq hdaiolosic.l drsrdia, 

e€ight gair dd nclalolic syndrene followir8 lr?icil rnd att?'d &nFycholica 

hailndt, is al$ hiehlig}rcd. 

Tt. involvmml of the dopdi!. r@@ror D2 (DRtti GC I I M I 12'785) gcle op6 up 

$e porenti.l for a trgeled pb@@g6ohic rpprc*h to ihe tr€atmcnl of $hizophrcDa, 

pcldlmrric *ess dierdd, ftovm€nt disrd6, higain ed olh.r psychotic 

dierd6. Regulaiion of dopmbe plays a cMi.l ble in ou nnlal md phrsical hcal6. 

It E e live l@M dopuine R4rou, clsifi€d inro "fdili6" on tlte bab of 

sjmileit€s in eBn 's.qu6€c ed fu.rioni cflals, The Dt fdily imlndc. tne Dl and 

D5 depto6, whilc rh€ dopuir. D2 fdily includG D2, D3, ald D4 M@tos. Of 

d.5.,lhe dopdinc D2 fdilt dd in pani.uld thc

tncalaiic lcspome of anriprrhofic drug!, which so fd remaiB elusiv€. Th. rcpon.d 

r mne poin6 our a dispsity in rtc pDponion ofAl .u€16 berwcn,a.€s and 

nrt'onNlity. I decided to inv.sri8ll. rhe frlg!€rcy disrriburion ofTa{ I A potynophisd 

of dopmine D2 rcccplor gqe in schircphrcnic paiicnl! on tonSrm bqhrnt of 

atipsrrholic drugs &om d€ popularion of K@hi. 

'Iltb study will pDvid. rhe euidetinc for the €fierivencs o, drugs. lh. il€Br@ ofsoleriry 

of rclalcd side cffecG, &d rlcir cffccr on diffc,enl pa@dc6 lilc neuot@shin6, 

@nccntr.tions tarliculdly wirh rcfcrcnce ro thc halopcridot and clozapinc. tr is qxp@lqt 

ut t 'l riu .l$ prcvid. beti.c d.r. for d.rmining htulotosrcar d)s.sj6; whi.h ic 

cntical in ordd lo dcaiSr bctts s@oing prcccd@, doe moflbnng ed ro pmvidc 

h@alological sf.t, lo dercse morbidiry tud donaliry relatcd wilh lbse Mdp!),cholic 

I.2 RNYIEW OF IIIE LITERATURT 

1.2,1 Sch@phreri& SynDroDi pdtitr. rrd N.srrtv€ Sytrdroh. s..1. (pANSS) 

.rd Ardpry.horic Dmgs 

Thc mliFycholic dng5, Eed 16 Etal rhc aymplons of schrzophMq arc d&rimnDrd 

inlo lrlical tud aq?icat etipsrhodcs on rhe bsis of tneir lhmpeuric cm@y dd 

peptuity lo indlce erna prranidai sidc cllel!. Thc cficacy orlypicat dnripsychoric 

dru$, ptrliclhny halopcndol h6 bcn showtr lo coml,rc wi$ doDntrri,rc rcccpror 

occuplncy!trd is highlycrcclivc aor UE trcllnul ofposirjvesyDplon otsclrizophenia 

al tlltiv€ly low doFs, Dd€ such as cloapine (rhc so ca €d arrlicat e$psrchorics), 

elfetiv€ rowads rh. n.8arivc s),rplotu of sbj@phhia, hwdd, har€ Flariv.ly low 

afllniiy lo D2 @cpior dd $B have a lowd pmpdsily rc mducc exFa pyrddal 

symplo@ (Fard. .i at., 1992i Nordlrrob €1 al,, 1995). 

The nosr qidcly osed n€rhod for thc shdardircd mcrnrtumcd oi odrc syt)l|torrs r, 

&hizophrcniq &cording b thc Ancdcd Dil8troslic and Sr.risticat M4uat of Mcnr.t 

Disordsjv (DSMlv) j! PANSS. lr consilul6 upon for eal6 hnvjng 30 irchs. 

mwlnng 7 pcirivc synprons (l8 ucination, dclusion, diargmjzcd specch, Crossty 

dis€diz.d or .ltrtonic bchaviqi uulrt holor b.havio(pcin& @kind ed 

dep€Mnalianion or der€alizalion.), ? negadve synplons (oat or btut.d beb.vior), &d 

16 Epffiling difldc id d(vor eqnqal sddiiy of jlhe$ on lh. bsrs or rwo

€lablishql psychialric mring sydcDs BPRS (bn€f psrhi dc rutinB scalc) dd dr€ 

Flchop.rholotical 6tios sch.dulc. .nl!s providiry bateccd Fpre$nrarion of $cc 

synplons dd rhen rclationship !o glob.l psy.hopa$ology (Tuga.l alj l97i Ms cr 

at.,20@). 

Th. dcS.live srrptom of psychoii. dijordc have bco dwi{.d vi(h thc 

hyr{doDrninergic alarc and could bc impovcd usjDs drugs urrl drmhish scDbnqBic 

&trvity, likc scmbft dlagonirrs, A! th€ lowding or scoronrn ,outd rsuh in I 

dimi.ution of pGirive $d/or neFtive synpto,ns sinco smroncryic afcrcfl ncurom 

syr0psing widr dopamincrgjc ncurcns cxcrl d jnhibno.y cllrct. (Carpcnrci l995i euinrin 

cr ar., 2004; Rclrolds 2004). 

L2.2 DRD2 ..c.ptor g€o€ potynorptisn itr Schizophr€lr 

DAdincrgic nc@tr&5ni$jon is.tra.d ,n a Dbb.r or ,.!rcto8ical ed psychiaric 

dtsordd inciudirg schtophMi4 de8 ,rtdi.ri@, al@holsn, ancnfion dcficir 

h,rtutivily dibrdd (ADHS) dd p.rki,sn,. disde (Comins cl at,, l99l; 

shalhoErlgoli cr d., 2005; p@tu et .1., 2OO?) T1r n€rap€urc nspotrF dd lh. 

ev.nty of adv€rsc symptoms of atipsychoic drugs wa hodllat€d by lhe gendic 

vdidts of D, @A[06 (Kaiscr et al , 2OO2; Lencz el al,! 2oo6i Kandet, l 9l ; Hwong el 

al.,200s) 

Dopdir€ h}lotlBis p$lulal6 h}p.r& vny of dopdincrs,c neurcranmision dr D, 

Eepto6 dd prcvjdB

The genetic @nt ibutim i! tle eliolo8y ddor pathog€nsis of ehizPhmia h dillcml 

clinical sludi6, lh. noleul& @han@ of lhda.rHlic cfativm* of 4lip6ycnodc 

dag and advmcF in ntud d.v€lasot eucg€* rn€ itrvolvemdt ol diffcEnl san6 

lik dopdin Bcptor, ffironh Fcpror dd nc@Eopic f&tor in shiaPltroia od 

othd mot l illnelg. (virsos .l al., 2001; wong cl d., 2000: Pclronis 2000: Klpckki, 

2OO2i Ho.nicta ei al., 2006; S€ri. e1 al,, 2004 Bistfoi el al., 2007). 

The gh6 i.rclvcd in lhc dopdinc lrsmisiot dd developnol of tic bFin @ 

suegdt€d lo be Ue cddidatc gpr* contdbding in pathophFiologv oa Pst€hialric 

dis6e (Cordis €t d., 1990, H.ser .t al., 1999). Thc DRD2 s€.c is a cudidd€ senc for 

$hidphroia b€Ne of its polarid .trnjty b*ards dill€dt ttD6 of mlipsFhoric 

.lrug! (Cal!l&o €t al 1992: Hauge €t .1., l91i rlidei €t al, 2002; zharB ct .1., 2003; 

The DRD2. DRDI md DRD4 e the oosibl€ c&did.te gd6 in ttdive dlstineia' 

ext6pltrdidal s}tldene, t rdive dyslooia dd rclrol€pli. nali8nml svndon€ 

producing rhc lonS-lem advffi elTels of mtipstdolic ddgs l!!t e D2 e@!or 

bloctd Mih@ el al., 2002; Kishida .t aI , 2OOl; Slali ct a] , 2001; Gmi'-B{celo el 

al.. 2001i Dubertet el aL, 2004; s€cD4 et al , 2ooo, 2001, 2003; Nat@no 't al , 2005) 

Th€ d69mire Bl @.pror gde *6 .!so @6idd.d d a mdidr c gac for 

enidrhrdir b4.@ il wd found lo b€ !p cgulared in pctnoncn br'in dd h4 

amnny fo! .lozapin€ (szcLdes .t al., 200,4 dd clatt et al . 2003). 

rh@tt?ic difreM6 h.ve b€tr 6*iar.d wi|h dopdin @€pto. D2 gcnc (DRD2) 

vdiers includinS reduccd D2 dop@in€ t6.pbr nmbdt sd didinkh'd slo@* 

n tabolisn in lnc bFitu of subjats ouving the DRD2 ,{1 allclo (Noble 2003) Tnc Al 

alelc ot rhc DRD2 epn. k th.ugbl to rct 6 I nodifvirs go' 6lha lh{ 6 the ldmrv 

ctiological .8dt in a nbd ofb€havioral drsdd (ConinS '1d l99l) Howevd in 

dfl8 addiciioo @d shizophrcnia lhe PBaldc€ 

or tns Ar allcle wd onlv siCnificot 

*n n 6mpd€d wrLb non al@hot. 6nhL dd wbo no 'otrlDn wd mddc lor 

munipk conpdi$ns (coming cl al l99l) 

Thc DRD2, Taql allele Ar, ldalql noE tn& lO kilo b$6 (kb) down *Em non ihe 

@din8 rc8rotr of ll|c DRD2 sdc, ws !@rlcd lo bc @i'led wid aloholGo ed *iil' 

inctwd slsc€plibilily to poly lubsl&ce dd cocsinc abse (Blun el al 1990' Gejmd el

al 194). A si8li6cmt pblongatim of Prd latelcy and dininish'd vissDalial aliliti6 

sussBted thc Elalionship of Ar allcle of lhe doPmin DRD2 g@e to phdoltTi€ 

qprBsion of DRD2 in ihe cdd!'te nu.leu (Nohle ct al.' 1994) 

Th€ odils rcei@s ed sglicejuclio !t 36 copi6 oflh. DRD2 3@' wa scquoc'd bv 

SdlG er al ( l99l ) .d tue potymryhis witbin lhe so' vft obeded bul mrc wd 

tholght 10 affeot prot€in sFuctur€ dd cxpGtion DRD2 @ding sequocc abnodtlit'es 

w@ als as$i.tqt with atoholisd d &hi&phrnia (Gejmu el a! 194) 

' 

Thr 

wiels wqe r@oned &r1 pode€d at1€Ed eirc &id *qu4'4 in th€ r*@to' b!1 

none wft Bscialed vith al@holis or $hiethdia The 9o01}?6 A1Ar, ArA' dd 

A{A{ ud lhe elAti6hip h€rws T.ql DRD2 vdrts s' clinic'l svnpbm and 

pathogeetic f4turs of rhe patienls widr $hizod!€nia did ndl cobtm lhe ssFho' 

b.tw@n DRD2 gc@tyP. md ev of th€ die.des ltudied, but Potendal 

gonetic rillot 

' 

involvcd in tne susqtibility to $hi4phMi! wd &A, DRD2 sdot!' (Gotimbcr €t 

d.- 1998). 

Linloge oslysis hG bcen mlde 4id qith ihc us of eitldion ftagndl len$rt 

polForyhi@ (R'FLPS) bv sFcilic Grriction 6do clcas (G'rdis €r al-' 1990) 

Cenu Datt fts of ih€r fragnoL mav be ir&snilltd $rcugh fmilies along w'th a 

die& sdq indicatinS lhe l@atioo ot a vd&t gdo wnib 6@iaion 3ludi6 sueg6t 

th€ &Ecu.tuy of a paniculd al1.L dift@ in a poFlarion or alf*ted individuls lion 

dal s@ in a nomd conirol popularion (Codis e1 d , 1990) 

Tnc bws dtuiy ed dibinistrcd turcriotr of DRD2 w6 N@i't€rt wilh rhe A' atlclc of 

Taql A, hov€v.r DRD2 pobdorphin d@3 nor plav & iFponel ol' n 

prwhopalholocrca! svnpiom6 of $hizopnMG Guzuld el al ' 2000i wu ei tl ' 2005)' 

An @i.fon bcr*6 dopmine recptor gd' sd *hi@phr6ia wa @cntlv l)d 

reponed b.twen a pubtive fwrioMl Dolvmorphis tl41 C In&'Dcl) U8t nav afisis 

swcDlihiliiy to $hizopbe a (Jon6en et al l999i Ari'mi 't al ' 199?; Ohda et al ' 

1998. Ts.tati! el tl,,2004) Thi! g6.trc !d!ri6 itr lh' 5 fltrking Egion ofthe DRD2 

sdc drt nol a pl.y tujor ml. in tlc g@etic pEdbposirion to shizophEda (T'lldi'o el 

al., 1999; Slobq cl al., 1993). 

DRD2 scn polynoAhim ad rhc clinical EsaoM or rrypical dti!.Y.toti. drus 

clozaline de rct seiated wnn e&h olh€r but dhplav hi8n afiiniiy for D2 rccep[os in

the linbic stst€m (Ar@ er al., 1998; r*patis €(.1.,2004). Nc8aliv€ alleli. @iation 

ws E?oned belween ! singlc be d.lelion 141 dolla C i. tlte pmmoto region oa lhe 

DRD2 g.@ ed $hizophrenia AldFugh ir E ml a siSnitrcst nsk f&ror bul a sltons 

cudidal. for rcwdd rclated behavior lit drng abse ot for shiaphrcda (Li €t al., 

198} Th€ o$4 of ehiephhia hay not b€ innlncld by the DRD2 g.n bnl lhe 

symptoms of ehi@phr.nia wd€ sigtiic&lly influmc€d by CytSl I .nd -141C D€l 

iHinei e! al.,2002). 

A pobmorphtum tu r non@ditrs Ar alclc of lhc Taql A Egion of lbe DRD2 {a 

obseFcd i. wc6l studi6 ssiated ei0r atcoholi@ &d subsL@ abus. R*uldng in 

ldDdarion oI dopminc trmsDision. which mighl declle the dp6sion of tn€ D2 

@€plor aae 

in respoM to Taq I Ar allele nuLliotr LinL8p disequilibrim bul Ellica& 

studywerc failed to confim thi! dscialion (Ldelle d al, 1998). 

Arimi d al., (1t94) had retoned a posilrve Miation b.tvq $bibphqi! od thc 

Cys lrl veidt of th. DRD2 s6. but olhd stldrd do not suppon uns t'l'tionship 

(L.llHt ct al,, 1994; ltin€i d al.. 2OO2). It w6 also indicded lhd the ftcquencv of tltis 

godic veial is bi.5.d gogr4hicaltt od musr lh@IoF be @Nidct€d *ha 

ihvGtigating lhe occmce of eoetic vdi4ts &d disee (Hamo 199?) 

Thre nw go. v&idts have bq di!6vdcd fd DRD2 ir iDtron 4 intron 6 dd qon 3' 

in addition 10 th. t om Taql A elricdon nasrn@l lmdn polvnorphis (RFLP) sd 

exon 7 (31 1 Sd/Cts) (lirckh el al 1996) Rsent sludi€s suggcst lhat the Taq Ar allcle 

dil lhe 3l I Cys v{i&l @ the onPoddls ofdiferdl grups of h'aplotyp6 though both 

vdidls rc slsulated !o b€ d$ciaicd with .lcohohn or schizoPhMia 

Ille pollmorphL DRD2 8oe vddll w@ obsd.d pFdi'lin8 lhe dim &id 

suhcututos Valao >Ala PnJlo...set, dd SsJll >Cvs in l!€ Eepd pro'cin 

chdaclcizerl by redu..d abilily to etivate the appropnate Gi_like Protei! dus plaved m 

imporrdr reI. h the Phm@locical implicadd of D2 6@tor bl@king drugs o 

enizoDhmia &d orh.r pstthi.t ic disrd.6 (CBvchiI( .t al., 1996) sttutural chde6 

s@ not obsdc

1.2.3 N.rrotrrnsml(eB .Id A.dFychoric Drugs 

An eiafion b€t*d cnain psrrholic illn*6 (in tudins misEin , deocsion .nd 

&hizopbrchia) dislurbdce in minc mcl$olism in the bnin sd & abnomrhy in $c 

ne$ylltion of bio8oic min€s (talriculdly erolonir/dopdine) in $hi&pnmia has 

long b€. @cidsql (Mctrz6 .r a[, 195; tqb.l d .1,, 195; Abi-Deshm l99t& 

2007). ft€re is also aiddce that dcGsiv€ El.@ of ttE pulative n€@rsmitr.r 

dopaminc (DA) ad d€ficimcy in saoronin (5-lIT) tunction ar. r$ociated wilh 

schihphrcniu(l|.$ogi, l98li Ladcllcct !1.. 2000). 

Most ollhe action of phmcological agenis ued in af..rive disordds hd b€o @tar.d 

ro tcir crel o. biouin6, which ee bcticv€d ro &t s neubrEnsfrificr subrranccs in 

dc6 otb6in nediaLc{ (thc linbi. syslcm includinShr?orhlldus dd o0rr fonctionaly 

rclaled bmin rhcturct, behaviont tunctioN (pjctclmd, t979). 

Tnc pDpc.d 8dedl mehsi@ of drypical &tp.,rhotic dD$ i. th. sDbni. c.ptor 

draSobi.n @fiributing !o rhc low dr.aplrdidal sid. efler pnfil. (S.sm& er at., 

2003; Mortima 20Ol; AhiD&ghd 2007) ho{cvd, rhc cla$ical dlipsrholic dogs 

have $. pot6li.l lo irdu.e qt ptrdidal sidc ef&cls by dopdinersic @erlor 

bl@kadc (Wu €t al.. 2006; Gu6 et al,, 200?) S€roronereic hodularion hs bccn 

.s$i.ld with rh. iD.@c Fl€e of srriltal dopmiscr 4 dopein Elce in the 

DEftontil cond can lffet the ncgdiv€ dnd coanilivc stftton$ ofschiTolhrcrin rnd 

@ bc hoduhted eilhd by rhe @mbincd 5- T2AID2 rtplor ml$onism or rh. 

pEfelehlial blockade of inlibilory dopdinc auto reepron o. D2 .eccptor anbsonish 

{Ho.rccL el al.. 2006). All thce cotrtEdictory obscry.rions lcld ro thc postrrtarion ol 

"Seotonin H}?othqis or Schi&phMit' lh.t ains to cxplain rhc htlerncrvily syrdomc 

Gchi/.fhroni!) on lhc b.sis olincrc$ql scdonirr Nd tryDbphu lcvol (shrnMcrrl., 

t991). 

Th€ all.olions in the lcdvity of nono@iD@xid$q (MAO) hd b.6 nosr qr€nsir€ty 

stldicd in El.tion lo veioE daral almfrslili.! s il involved in rh. synth6is of 5- 

hydrcxin.lole &eric &id (5-HjAA) - a Mjor m.raboli. prcdlcr of srctonin. Reduc.d 

plalelel hommirc oxidae &livity w6 oblded in chrcnic sohizophMics (M.llz.r.r 

al.,l9?4) in tun redkc @rrbolis of@to.io (5-HT) and iic@c rhc lcvet of 5-H|AA 

(l{usrosior {1., |,81)pdhul ly in Nsponsc lo nclrolcpric lrcllNnr. Mljor nsulnrion

oa 5-HIAA ws $tuugh tbc f.€d bEt mcchoisn .nd rll $osc druEr or subsronc€5 0Dt 

&hsonize thydbrtlrFtanine ard MAO (..9, LDOPA) .ould thd rhc l€reI oa 5- 

The critical blcor3colodn (5-HT)-rccepro.bd.d nehanis s dd lhc polmt 5-HT2A 

@eptor btosonis toeetho with p..k dopmine D2 @eptor &hgonism h6 ben 

Postulatcd 6. prircipal phdeological f@trlr ihal difehd.le rh. nq ecncBlion of 

etipslchotjc d&g! such a clozpirc and thc fFcg@darion of dtip$trhoric dn$ tikc 

halopcridol. s-lITIA .gonism w!! d inportel @scquqce of 5-HT2A dtagodm. 

which may alio t" produc€d by d.ttlpic.t dtipstchotic dog who coupled with qc.k 

D2 inlagonisn md lhus lower thc cxlreramidll sidc cltec (EPS) (l\4cllz!l ct d.. 

2003). 

Thc h'!o tunctioning of dopamircryic ncurctiesnision in nedial peftonr.l @ncx 

lllcviatcd byclozapinced olher arlipsycholic druSs w$c lssocidlcd *irh thq synpronrs 

of $hiephmia (H.idbred€. .r al., 2001 ) Tne cbz.pine-iiducod incrcsc ws ob$flcd 

iD lhe dopmin. @nc.nlration in Uc todal 6n€r whilc h.lopcridol-induced inc@c in 

dtrB-c.llule doDmin . DOPAC sd HvA conc.nEarion w6 obsd.d in $c auialm. 

Clozei.c qhibiis 3lto.g m@utuic dr.g@isl prFnic hut n doq nol poducc tull 

blockad. ormu@@ic r*.Dior in tl€ striltun in vivo. Thcrcfor€ thc interaclion of let 

of ability of cloz.lin. lo prcd@ EPS srnplom or lardivc d,rkinsia w6 Eldoi *ilh 

rhc choli@sjc sy$d in th. striaium (Mcltzq et d., 1994) 

Togerh* with D2 F@tor blocloda, th. chronic halopdidol ldninistalion lq& to 

de@. ba.l dop.nin Gl.4 dd nctr'bolin pFducing lolmcc lo h.lopcridol- 

induced incc.e in dordin. nebbolis in sltiatun bu not in nuclas .ccumbens 

Cloapinc hd no ellftr on b6al dopmin€ Elce dd nebbolnn bd n produc.s 

tolff.c to cloz.pioc-ioduccd incrce in dopdinc nct$olism in nucls accunbcN. 

Howsvcr, slighr d€cms in dop.min€rBic liansnission wN obsoecd h nklcus 

rcuDrbcns vilh @ncurcnl inclt:s in sl.i.ruN lncr chonic cloapnN t@LnLl 

(lchikapa d al., 1990, Compto! e1 al., 1989), A 62% d€clls in do6al skiatat dopdine 

Fupkl Ble qd obs.ned which may bc Elatcd b fic motor side .ft@l prclile ol 

h.lopdidol tr .tnat whil. clozapinc had no effet on uptatc nt€ (Rorhblal d al., 

r997).

Nondr..aline ha bo shom ro onrot dopamift tutw.r .nd alce in Br b6in 

(Sri,'i!$u ct al., 2m4). Tlrc cxls-@ttutff trolttdrunotiN wf,\ ihoMscd in $c nrqtid 

Prcftonlilconcx aft.r adminisdalion ofdripsy€hotics &d w6 explajncd by inhibirio. of 

5-tfT2 r*cpior dd mr dopdin D2 d@!o6 (w6rdink er at.,200I). 

Clrtonic halopcridol kcahcnl incrcN6 thc nunlbcr oi D2 Mcplob rhitc m inoMc 

wa obsflcd by cloapinc. This sugS$6lhc porcnt 5,t.tT2 recpror drlagotrism vc&s 

wc* dopiminc D2 rceplor blo.kadc or the altscnrc ot lFrcgulalion oa dopminc D2 

@eploE (hhikd€ 1998). fte d.daric increGe in srrialal dopminersic ed 

'@londsc tutuvd (toh.&n. 1992) .nd & inct@.d sluhindSic tuncrjon wilb 

dopqinergic @eptors bl@lade following nigh dos w€re rcpolrcd 6 ti. pmpos.d 

modc of&tiotr ol tt.lop.tdol (Jls ct al., 1993). 

Abough th€ ble ofrtlbtha dd 3@ronin ws nor conplelcly udmtood, tne cfler 

of eliprlrhodc may ren€ci iheir involv.mar in lhe palhogdBis of ps'€nodc illn€ss 

like obsive@nDtrkiv€ di$rd6, alcoholism, de'lsion a violace (Licbemnn e( 

!1, 19931 Kcnncdy cr rl., 2002). Thc parholoBy of dc(ced tr}?toplun nnd $bro n 

wG conclared widr inct*cd dopMine since a tunclioml linl bclwefl dopanline 

drrvily ed sblondgic n.mN in bEin ha aledy b€o 6r.busn.d (sntdd cr at.. 

l r74j Rrtosi cr al., l t8 l ). 

thc cdlal rclc ofmultirold behavioBl rcguhtion pl.ycd by scbronin md trrplolh 

pciphcral oncenlrjlion w6 aho inporlmt lor nonnal loncrionins ol erclonin 

ncunlmoislion, whicb w4 in lum adjlst€d by heparic md non-hopdic rrr?lophD 

pt@le &d rclce of Frploph& fton dbmin dd irs plsAe a!16 ihe bl@d,b6in 

bdid (Sr.add cr al., 2001). Ioc@c in the &* pool ofiqlrophd hs b€en r.pori.d to 

inc@ rh. bFin s@lodn lwel (Iaglido € ci al., t97l) nobvd fouowins diel- 

rnduced inc@ in lry?lophd 6uld inc@c thc brain soton*sic rclivny (Maltls cL 

r1..2002). 

A d6t€s in bFin $b|onin ed 5-H!AA ldelr induc.d by gluco* wd obsrycd but 

lhc hrnnr lrtlxophatr lcvol wls rbl d{rc$cl (t qucr cl rl., 2002). Or ltr uoDlirry, !n 

ncl€4d avajlabiliry of Fyplophm w6 obsfl.d with .on lmt incru. ih b!.in 

@rdin smlh6b following c{bohydrdc dch di.t lhoud r stull mou olprorein

wa sugg6l.d 10 bl@k this mahdis Endqine it d u@moi Epoe (Bdlon.t 

^1.,2002). 

Thc &tidcpMr &rivily of rypl@hd my phy a ml. in nild lo nodcr.te deprcsion 

by dercains 0re aegr€sion (You.s er al., 2002). Sinihrly patients tBrcd *irh 

lp@ific- eolonin- reuphkc inhibiloN (SSRh) @ovqqd rroflr dcprcslion, silns ol 

deprcsion w€re obsded followin8 acurq lry?rophd d€plelion (Berj ct .1., 2002) 

Try)roph.n aDd scrobni wcrc cotrsidcrcd $ nil ul rlrcmrlilcs lo m(irionrl 

ridcprtsnrs, which can bc osql lo @lvcd unipolar dqrNion (Shaq ct !1..21x)2). 

Livqr lrytlophaD pynolsc ws cotrsidcrcd B orc ofthc prirtipnllelor lhut alT6k brair 

solonin synrhEis by alldins $. lvaibbitiry of ry opne b lhc bnin susg.sing an 

ihv.M Elrrio. (Bs&wy.r al., l9?5a; c@n et al., l97t; orelti cl a1.,2000: AllceF et 

d., 2003). Ar inpaindt ofbnin kdoFnin prrhway in ehi.ophr.h hG ele bm 

Epolr.d r6uuing in el.vat.d kyndmin levels (schwdz.t al.,2col). The ircl€e 

tynlMare ws . comequmce of inc@cd trrptophd lumovcr, which Bults in low 

bRin tryplophd, dd hd.c @tonin ldcls in shiapltenics (Moll€r 1985). 

Trplophd chrcnically rcSulal6 thc activity of q,piophd PFolde by prcducjn8 a 

subslarc r,Ijc cnharccmcnr ind by tl€rcdql dcgnddion olDr+.risttr8 rrbcMynrc ar 

$e prcehccofnomal rat€ ofns synth6is, An enhanced elivnt ol lrtplophe pyrclasc 

E ob*rycd rollo*ins hmalin or s-mirclamlcnatc (hme pr€uMr) adminisrnlion 

exhibic a lareer dcsree of hcm€ soluration thN slggcsting a 6l€ oltrlTlophd tydoltsc 

in urilizaion oflirrhcme (Badawy ct.l., 1973 & 1975 b). 

Trr?loph& p)@lsc erivily wa.s signilicdlly innibn.d by anndeps$ls od d 

incF6e w5 ohsdcd by the ad inistdion ofacub elhdol, adrchalinc, nomddalinc 

and salicylatc (Bad.*r ct al-, l9?E & l9?l)- Cl@.pirc Elared ftilit tion d inlibidon 

of e€niral tegmmlal dopMiDe f,euFtrsrnission dcpqding on the btain concolration 

oltynllMic &id hay be Elared to irs uniqu. ef€l i. adclioal'n8 ne8.t'v€ synp|ons 

ofschi^ rcni! (Sdrwichr d al., 2001). 

1,2.4 H€mltologicd Dyrc.t5ilr rnd AtrtlFychotlc Drugs 

A major oblraclc for th. us ofnlipsFholic dtu$ is lhc ldvm dtog Mclions sucb 

blood d,&r!si6, htleGensitivity dnd €xto prflmidal side af€cls - a major cluse 

paridls morbidlty ad modality(Cscy 197; willi.s 2006).

1.2.4,1 rDtr D.lict.ncy ,{n.hi. ,nd Typt..t AnrrFrchoric .rrearm.nt 

Halop.ridol lrc.r€d pariqk havq shom highd lcv€ls ot deprc5sio., hr?mnnia nnd 

p@lrsc (Comelius d al., I93), whil6 ctozllhe is Nciar.d wirr ! vcry tow i.cidftc 

of€xl8pyrdidal elfer (Alfae ct al., 1994) blt bs levfrt wc[knoBn ab.omalilics 

orbl@d.ell cout trairopcni4 qmulocytosb and Oombocytoris clc. (Assion .r Nt.. 

t196). 

The hcmabloSical riskl 6s@iarcd wnh cbapine panicularty in lrcattoenl_resistait 

el'idph@ia in UK e tcpt wilhii @q,hblc limiG by pariclr monilorins $tuicc 

(Alkir ct!1.,1998). 

An undc6l!|ding of lhe p4lDgcncsis of hcmarologicat dy*hsi6 i! csenlirt aor $c 

crecrivc maaen€nr of halopoidot (pal!o! c1 3t 1994). Ar adv* Eerion, including 

h.natological oetlicarionr rcport d by conbonly pEcrib.d ncetcpric dru8! w€r. a 

liniting faclor duin8 acurc and .hbdc rrarn6t, which ccudld inf,tqucnlly btr 

rEmN a poGrdal c.u. of 3.nour toxiciry (cey d at., 1996j Kjng.t sl,, 1998r Brlon 

ct al., 1987, Kwin 193). Althou8n lhe dsk liom mosl drugs is snall, il n.y ,fiet 

periph.ial blood €clk &d bo.e nmw (Lubtu 1939; Sub.f elat.,2004). Mono- 

$mp.unc ucatmcnl of d acllc $hizophrcnic psychosis wnt bulyrophcnonc 

(h,lopcridol dd bqpqidol)

@iely &d dec@d cogition dd altenlion d the synploms N@idcd wi$ non 

d.lici.ncy ftponcd in ldulls dd childrd's (Bs.d €l d-, 2003). 

Son€ evid.nc. sugg6|' a relc oI itun d€fici.ncy in lddiv€ dyskildia dd atalhisia, a 

cilmon erlr.pFdidat s'dc €fi@ts ot d6sical &ripsrcholic dn$ paniculdly 

halopdidot, 6 hieh prcvalmc of itur defci@y hd be.t r.!orr.d in lhc pdi.nt ol 

etl6s IcC! syndrcn., a nerclogical di$rdq cne&iaiz.d by a dislr€sing icistiue 

urse lo movc $c legs (.t lbisia) (wiEhitrs .t al., l98i Hotird cl d-, 2000) 

Iren is osenlial for prcpa CNS nelabolisn, Ihe hei@gdeity ofunev€n distribution of 

itu in hMd .nd rilt b6itr suggBlcd rhd ibtr my play a ftnctioMl Dlc itr agions 

ri.l y imwarod by dop@ircrgic Dd CABA4ic nercG However, lhe 

n@biolosical n6hdim bchind iron's rlc in bchavior dd cognitim Ehais elsive 

A loDS penod of rcgative ion bal&ce, culDidting in dhaution of the bodv s ircn 

rloq cuh in IDAi &c sedive stag6 of ircn deicimcv m ion dore depl€tion, 

ion d.ficienl d),thrcpois6 dd iron deiiciency eeni& Diaetosis {d cor@lion of 

udfityilg cal$ hlve inponet inplicatioB for rh€ @Strilion oI ion deli.i@v 

ddi4 poopl€d by hi$oncal f€lur€s and aided by 5p€ci6c clinical ud bboiatory daL 

(Gcbois e1 al., 2005; Jolobc, 2000), 

The clinical n.{iGslalios of irer d€6ci*y ed io! denoidcv dmia e vdi'd ad 

rclai€d to iti savqitr and dMtion. Whcn Itun defici€ncv dmia (lDA) dcvclops' il nav 

be nild olb g.s-llg/dD, moddate (8-9.5e/dl), or sdde (

1.2.42 N.utroDlil c.ylololi.lty rnd AtyDLd Artipsycholic Trerttull 

Cloz.pitrc .&i6 a his! dsk of ird@ing a€r&ul@,'t6s ir I to 2% of p.uflb 

(K.uanfl. cr al., 2006; AlD, dr al., 2001; (dc €l al., 1988), .dltop€ni! dd 

firenboc',topdia n I to 3% of pltiqts; dd eflia, Leuk@yosis dd thionboq4osu 

in 16 lns l% ofpaliois (Fiulimm er d.,2005i Bh!fl €r al,, 2004; Mtlowe €l al, 

2000). Thc &tual n@heisn of cloza?i.einduced sgtuul@,'1olis is not knom, but a 

loxic w frctor with ct@rdislics of e mtibody ws hr?o$6izcd a a pluible 

m*hdb6 (PisiotL cl al., 1992) atotrg wior liditaliotu (Liu el al., 195). 

Clozarine udergos dt .siv€ melalolilm ir s.r.l dpei6 including nd @d rod.nt 

biL, principally ro th. srablc m.rabolir6, ddelhylcl@apinc, cloz.line N{nd€ 4d 

scveFl other slucouronide ed lfate conjuSa&d (Gancn el al., 1971; Zhes et al., 

1996). In cultrc, diret tqicny bward cilhd polynorpniud*-notnphils (?MN) or 

rh.ir mr€loid prausc d. not er.hibit€d by clozapine, how.v.t N{d.thylclozpi.e 

ws noc loxic ths clozpire tow&d mt€loid cellq but iltis wa only obw.d at 

cotr6F.tio6 high€r tnmlhqc &hiwed rlr€r4€utically (C@n €t al., 1994). 

In hlm, clozpin wa nelaboliz€d b a @iiv. inlem€dial. by hepdlic cltochftft€ 

P450 ffiyn6 (Pimohmd ct .1., 195), ny€loid c.llr ad pciphsd blod PMN lo a 

radica! c.iioo md th.n nitrdim ior by tlF dyn€ m'tlop@xide (MPO) (Fiehq €t 

al., l9l i Uctehl 192). Eowad, in bddts ii ud6g@s ext 6ive biqctivario. by in 

vivo detsdon of sv€r.l gl arhione (CSH) cdjugat6 (M.ggs el al., 1t95, Lin €t al., 

r995). 

The nitrEim ior na b€ implicar.d in rhc parlo8o6b of th€ aereul@y16L- The 

inle@lior of lhc oiL€nim ion with a ..llul{ mdbnolecul€ nay l€ad! io eithq diMl 

toxi.ity or irdiEl imml@n.dilt€d loxicitr, althougl the cx&t n€ndis by which 

ioxicity @cu is ucld (Liu €t al-, l9J; MaCgs.r al., 195; Sallem& cr al., I92i 

Th. !i8h incida.c of dffic. of aSrNl@ylosis itr patrot! re

thc mtcloid linag€ hG ben povidod. (HotslE cl nl., 1993: patron. cr at, t994; 

Poum.ch6 et al,, 1995i Jauhtalns el al, t92; Adirymj.e t99tr pisciofta el al, 1992i 

cc6or cral,1994: Ilecglwl ct .1.. 1994). tndddirion,oncoalhctoslrtdcd eh isDr 

(cardi* er al., l98a-b) uodc yinS dozapincinduccd aereutoqadh inlolvos lhe 

cov.Lnl modilication of rcutrlphils/bon mlmw potcins by clozpin., eithd by a 

dist loxicity or vi. immdological o*hdism. For instdcc, the alt€ration in $e 

ftnction offie pot is th.r e &spoisible for rwival offi. cells, by the covalal 

bindirt otcloaDinc, lcirl lo ccll dc.lh, o! ir mighl bc possiblc rhdt thc imnNnc sysrcn) 

@uld ,cco!ni& lhii complq, sorcrurins nn litibdly- o' r uc nrudidqt u|bo* 

(lmliu ct dl., (lrD8n-b) h{v! toa)rlcd Ulrll p ictrls rrcrrqt w chrjpi,rc sh)ws 

clozapinemodificd polypcplid* a@D neutrophik. to vitro iDn,uDoblo(i,r8 sludid 

suggesr that th. aomation of difr.@r adducrs having not*uld weight anging ll,204 

KD a a Gult of covdo! bindins of clozalin. ro tme neurophils, lne, incubctine 

ndirophils in rhe p@nce of.irhq HOCI, HrO: or h!J@ ny.top.oxid.& with d 

sli-clozrpirc &tistu, In additio4 49 &d 58 KD cloarinemodified Ftypeptid. wa 

nosr cohnon in all. Mo@v.r. rhe .xr€ceuuh. sturarhione inhibned rhe bindins of 

clozrprne to n.unophik in rh. pBer€ ofHOCl, bul not I{rq w6 q.d ro g€ncratc 

wzni cr al., (2006) rcported ncuftph .riororicny in ots to owing chronic clozlrrnc 

rMlneni Th€ toric ettd ofdtus ws ob*d€d on neulrcpnjls wirh condqsalion and 

subsequ€nt brc.l

PUR?OSE OF STUDY 

In eqt y.c, e@h focusing o. rlE,ot€ of biology In ndral il.ss hs become 

ihcEsjnsly pdaldt. pdh.pl rh. nod studi.d tu rh. @merion btuq rhc 

dopnn,incrtsic sysrcm and *hiz.phEnia. is gcnch|y tuc.f d r0r E ptut.cftcd ctGs 

of hcdicatiohs for schizophrnia m thc tlpicot ad alyprc,l aniipsycholics havins 

ditl.Mr neubcnmicat Md flncronat popenics, b .dncc sJdptohi minimizc si

To |he b. ofou. kno*ledge, tnis is ttu li6r srudy ofi6 tdnd lhat povidc beli.e dra 

on eh'zophrnic p.liac 6on ou porularion, ued tbr b.nd und.Br.ndins oa 

ph@&ogodic f&roB thal influace! tlE lh@peudc qpose of trlip,rrholic dtuss, 

wii.h b fd h.i.r olusiv.! wjl alo help io d.Gdining hmarot6gi..t dyscrGiasl 

which is ctrical in ordcr lo d6igD bclrc, *r€enins pDccdu.es, dose nronrloring dd !o 

pbv'de hdalorogicat safery lc.dins !o dd6. moibidiry dd nonality rtalcd *ith 

Thc Dain objecrive oflhis $udy is rol 

I Dotctuine th€ psFnopatholosical mc6u.€s ofrhe shizophEdc population by usi.g 

a.ndard $senrnr imkummrs-paNss md lo cvit,r . rNtr rntNdrtrcc kn rhc corc.l 

diasnosis and lrqtne oflh€ di*e. 

2. ldD ily l-"q I A gctulylr ofrtrc De riic DRD2 rcccpror gcno p.tyul rhnr by 

us',g lhe pdyft€@ chah @cfio. dd a GtriclioD €uyDc drg6l rn pdasta,i 

population, ro 1esl signjllcdr dilt€Mc* in Taq I A alelc kequoci6 in rhe coolot dd 

ihe schi@phEnic poput.riou o. chrenic r,earned ofnabp.ndot 4d ctoapjne. 

3. Ei4he rlE mutarion in a 310 bp astne spanninS $c polymorphic Taq I A siteof 

the DRD2 g6e of rhe halopeidol dd clozarift rrcakd sht&pnrcnic pariors ed no.- 

ehimphrcnic contols by usinS DNA scqrcncins 0nrl)aris. 

4. DraDrirE ltrc dilTcrcrlirt clleb of ctrcnic lbrmcnr ol hatop.ridot and ctoapinc 

(both conh€rcjalty availabte tud purified totu) on bio@ines concenhnon Gerclonii & 

dopturinc) indificrcnr rcgiois (hlbrhrtonr us, coacr. nridbhin d sthr{m) ofnl bnnB 

by usin8 HP[,C-€CD. 

5. D.Emjnc rh. @ncdrltjon of E rr.9he i. bhin / liq dd 6. &dviry of livd 

rtpropnon pynol6. enzyhe in rclpon* !o lhe chbnic (2t dars ,M) reahent of borh 

comc(ialty avaihbtc eit puin.d fm ofhatop.ridol qd ctoapinc in hrs. 

6. Funho cbaracrdi& od exqine rhc bmaloto8i.al dyrcrasEs &ocrorcd wnh lhc 

chDnic rMrrndl of hloPaidot dit ctozapinc in shi&pntuc patiors dd dimal 

model G.ts), in ordd b cslabrisn th. b@line dlt tor hhabrosEd dylc6ias in ou. 

eh'epxMic poputaltoo in cporue !o sc m€dicarioE.

PLAN OF WORK 

The €xtcrimcnbl n€thodotogy dsi8. 

druss OsloFidot ed crozapjn.) jn 

The pgl o,e @v6 rhc sadic study otco ols dd $h,zophMic pati.nb 

cnrcdc rFtnor ofh.lopdidollnd clozrpioe for moft lhe 12 weeks fon 

psychialric notpn.k i. lGEchi, patisl.n. tr i.clud6: 

2. AfrpliticariotrofDRD2 gcncspanningTaq tAsirc 

4. DNA Soucncina ror lhc lde.rn€lion oa muurion. 

Duc lop.uc4ofavaitoblcdalaotr dE gcoclic b6is oasc 

1o {udy lhc e1l6r of rwo dir*nr &tipsrrhoric 

&hizophFnic pati.nr! ,nd uinal modcl (Rat) 

p,oned,o study a concisib,e nil:;;;;"-il::liTl:#;Hl; 

a:t cloapine rh@foE ii is iik d.d b look for rhe ilvojvdntul of drug rclated side 

ettels or $eir gcre$c iinuence. 

,i:::1ll:. "::T -**, "f ocuehenicar profirc by Bhs HpLc,EcD, ih eponse 

ro the chronic (21 da,s tM) &eatncd ofhatoDdidot ed cr 

!v, hbr. atd 

',dncd ron,, ii u,,,,,,", ;; ;;,":,flil, :,:,l",,::ffll 

ndaboller roOpAC. HVAJ, slonh !t rt! p@uer firyprophe). &d m€bborirq 

. .rrl.qr (sjons such a: hr?orhaldmus. 

a.,s1n.tuh. 

con.r, hrdhmin 

":, -T:_T.:**. ft lhdld bc mslon.d h* dEt in rh! p'*n, *o* w. onty rcpon rh. 

qurc ordopmin , sreronir dd qplophd in alt eenrion.d Egions ofrat brain. Ir 

aldrton, Fytroph.r plrol& @,rn. ctiviry ed thc @ncqFaron oftrDtopbd wR 

ars dd@in€d i. liv€. s&pls.

l lE ti.d prn of rrudy includq rhc asssmqt of hchatotoSrcal dy*6i6 in 6pon* lo 

th. chrcnh r€almdt of halopdi

lLr otwort-l 

S.hiroFhab Fds (n-120) 

frmicdlytled{i6 

,/\ 

/\ 

ILLp.tridol Comtsoh clo?5pi6 

(lB2) (1F44) (1,148) 

\./ 

\t/ 

*.*rJ-** 

By s.ltlng ot drdo Elahod 

I 

I 

Allplifcdi@ ofDRD2 ge 

Sp€nniog TaqlA litc by DC]R 

I 

t 

OlooqDitre ty RrlI,P! 

b Tq rB{rictio .rrro.n'cL.s6 (J' ICGA 3) 

i 

Seq!.rc|r8 ofDNA trnd.. 

. . Ir.rd.d.dbha|b@oft.rddEohi,.dtelu..a,qtbS. 

. /|! rdd od 6. alr.t 6.6.&g6ir dt &ldianedarbDoMlv. 

. rbrtkrt-alddm!l-drarLh.!.tadqi.Fd!bElce 

pftdo. forM! iti t2 Ela

Pl.n oI Work-2 

Arim.l !tdi.. 

Md. SFase Dswlcy P',b (N=60) 

Divided into fiv€ g.oups eivc$ chonic (21 days) I4vl lreitnent. 

I 

t 

crcIp r(cdrolr) ol-d phFlolosi.rl ,.tic 

GMp 2 &3 0.2 ns/Kg- hrloFi

Honrn stodie3 

$chizophdic Fdda (F84) 

SM f6 dplolosiol oni6 

rDq r/Dq Dift.a&rdd 

P|!tr of Work-3 

Arinrl s.udies 

MrlG sp6gir. Daql.y R ts tFlltd *iih 

halopsidol / cl@piE C{=60) 

Divid.d inlo fre creups crwo clrcnic (21 dars) 

I 

Gpn (@ntrols) 0.2-bl pLrsiologic€l sdine, 

GF2 &J 0.2 dg/Kg- hrlopddol fPuifi€d fotu/ injetion') 

H & 5 20 Dg[(g- cbzqiE (rEif 

t\ 

Col.crio. oI lhc blood srDples 

Vhol€ blod f6coopl€t Elood Cdd. 

I 

J 

tl.tr!.lologi6l dd ]|ldlr. Ldi6 

0q Pcv, Mcv, rlrcrl Morc) 

tmM-dlr n ibbL hj..tir of brqqitot rort ..d 6 S.= 6u sdt . 

tcdl@i.lt .dLbr. Trbla of .t@Dir ret{.d r Ocrt toB N.atrit 

'P'd6.d pqdr fm of h.ih hdoFitoiirct iE 6m sise 

I 

I 

I

MATERIALS A}ID METHODS

2. MATERIALS AND METHODS 

Ttisserion includca rhe matylicat ploccdurcs cdicd out h lhrs study, AI thechomicats 

lsed |hrcu8h our thc study w4 ofe.llriql Snd. frcn Signa (USA), M€rct, and BDH 

cheoicals liFit€d unl€$ olhwjs. Ddtionol. Auroclaved dcronrzcd walcr w4 usd 

thrcu8h oul the qp€nmcnlal work, 

2,1 Colle.riotr ofBt@d S.Dpt ! 

Thc blood simptB of rhc s.hjzothEnic Fljcnrs wcrc colr@rcd rm,r difcrcni psy0hintd0 

ho+itak all ovd Xihhi, The qudbmirc @nriinina rhe @ns6t of rhe pali€.ls w6 

obt!'hcd boforc bt@d sepling. Sel@ted paticnr6 met rhs oitcria tor lb€ diagnosis of 

*hrzophrcnir &cording [o DSM tV ad wcrc {iividcd inb rwo groups on lhc bsjs otlhc 

l@trldt. Th. fi6r gDup (n=92) of$hibphEnic pri@6 wd u.red onry *ith ty?icat 

etipsyctrolic dng (halopcridol) whirc r*oDd soup (nr2u) ws lreat€d wirh arr?ic.t 

dtpsrhodc dng (.tozein€) .c@ding !o nom.l ctirrcar pr.crr€€ idr moe rh& 12 

*er!, Trlo hom.l 6tr .t epl6 (n{a) w.e .l& obldned 

e rcrcEncc nol havina 

stmptohs orsy plycliatric dierders. 

llE diasnosric critd'a w* elaltirh.d on $c bsi3 

s'idrcn€ *.,e (pANss) &cord 

""," ;;" il;;;:'"H#ffiru;Tl" 

A golt of psrrni{risrs Bi*cd rhe oedical record and whcrc nec€ls.ry, inrepicwed 

th. parials, The reo.dj of Oe rhizophMic paridrs wcE aho lsed b d€reminc 6e 

dcEosraphi@l che&r4isljcs of the parienrs, ase al rhe fid otuct of jlln4s. dlmdon of 

iUn6, duration ofatipsrrhoric tc,rmcnt rd cun€nt daity htrpsycboric drug dosage. 

2J Dop.Di!. Raeptor C.ne (DRD2) potyDorpbirm by p,CR-RFLpt 

Dd@inario! ofnrctcic a.id *4uoq dd rhe ch.r&lsizaxon ofgen.s havc pnvid.d 

a 

'najor rhrut h rhc undesbdins of$. bioloSicat D6be,ms of€cll. Recnr ldvancs 

ib- PCR tcchnotosy pav€d lbc way b sltdy $c cc al moteutd lcvclby m&ipuhrion of 

RNA ald DNA, including jc hotarion ed chdaclerizalion.

2.3,1 f,xftrctlo! of cdoni. DNA fom Whot. Bl@d 

DNA @ cxrrercd fron 3-5hi of EDTA-@lic@gut.ted vdoc bt@d uinS. satring 

out €xlr&lion n€lho4 b6ed on Milla, Dyts ed pol6ky (1988), 

RBc Lysb Buila {t5snM NlLCl, Io,nM KHcor, o.lmM Na,,EDTA ptl 8,0): 

8,2s NtLCl, Log KHCOr md 2@Fl Na,EDTA (0.5M) wde disslvcd dd $e 

volm. w6 nad. up ro I L witn distilcd ware. 

Wah Solution (0.15M NaCt, 25nM T.is, O. I rnM N& EDTA pE 8.0): 8.??g 

Nacl25tr T.is(lM)edIr N&-EDTA (0.5M) wft distvcd dd lllre votmc 

wa nad€ up to I L wirh dktilled warer 

SldiM EDT . Tns 6ET) Buffq (lOnM NaCtpH S.0,2nM M,EDTA IOEM 

Tn4: 0.8DrNact(6M),2ntN.:-EDTA(0_5M)&d5blTrb(lM.)w@dislvcd 

tuld dre volmc wa nade up ro 5o0,nl with douhlc disdlls

lfq tud vori€x€d ro di$otye, To rhis lOOd SDS (lO%) dd 2(]d por€inse K w6 

add€d, hixcd ed incubar€d oE tuBh .r 37oC wirh con$4r shatng al | 80 Dm. 

At thc eod ofrhe iicubadon, 500 At NaCl (6M) ws ddd ro mc etubilrz_oj pe|€r an{i 

nrixql by gorllc vorrqxirg. ltrc nrixturc wu lhun oorlitlguit 0t El)1t08 tlr t5 riruros 

looc. The sup@ata p$ couccl.d inro dother tub€ dd mrxed witn I mtofice{otd 

crlr ol. fic sotuliotr Ms gcott, mixct by invsrin! (hc tuUc un(rt thr. irc DN wJs 

prcrplllcd. DNA ws cotil.ugcd ar 8000g for t0 ninutcs, thc supcmatu w6 

d€dnrqd. Thc pctlcr @nhining lhe DNA w6 *ashcd wrlh t-t nt of icc cotd 70% 

clrr@l md ajr dri.d. Th. €xt rcled DNA *d d,slved in d app/opriare dour of 

.uroclsvcd double disrilt.{t waid /TE bufd. 

2,3,2 D.rernhrrion or purity otDNA 

For estihation or DNA, rhc oplical d.nsny w.. mcasuEd or joonm and 28onh on a 

DU-600 spetrcpbotq€rd (B*t be). tte fousina fo@ura ws o$d: 

DNA: O.D.26O Unirr l= 50 

PtrriIy ofDNA ws fr€suEd Nins thc 

2,3.3 Analy|b otDNA Int.gritt 

DNA: 

o-q26q > 

o.D.280 

EDTA (.rhytcnc didii€ tclhcclar€): 9.3g wE disotv€d rn sont-disri crt warcr 

and l,re pH va adjuied ar 8.0 wnh ediu,n hldbxidc (Signa). 

,rm ooar€ erhykrc dimine lek&elgk rrBE) pH 8.0 tux rBE to.89J!4 Trc 

oae,û.ueM boric acd, o.sM EDTA)j Tns (hydmryt mdhyu mdhyt@in. 

(i'd.ug). huric JcrJ (55!) 4rn, (0.5M, [D.tA wJs J,sot\ u t tr, dNx ul * ur 

Jn'l rltr finrl \ otunc wN madc Lp ro I L lirh disri qj \arq. 

:, ,"1: t*, Bonoph€nor bruc (0.25%), xyrcnc cyanor (0.2j%) md 

sucro* (.l04oq.r ) w(disotved In lOOntordrs! cd qarc, 

Elhidium brcnid€ staining 6ollrion (lOEg/mt stock).

. Mtld: oX lt4 H& IU Dsar (Si8D): 6tl w3 dielv.d in lqrl g.l lolditg 

l) M.rtod 

bufra .nd 36.8p1 lX TBE. 

29 of.g.@ ws di!&lv.d in lOOtrl ofTBB cle!!Pbo6i! bufi6 in . himwrv., Ihc 

raDpd.rN ws ltlov.d 1o drcp dou lo 60ec. TIE 8pl w Pourld inb r prtcat d 

&b@irc s.l srt&D (Hcffd HE99). Lm.dirtlly ! c@b ws pLc.d.ppoxin&ly I 

co e.y tlE th. .d8e of t!. sel tny. And ilc 8cl wa $lidi6c4 l[. @ob ws 

@ov.d .!d th..letophcir qpntu w fllcd M(ll IXIBE bufta Th. sPl6 

a@ Dir.d witl 8el lo.ding brf,... Th. .etl€ .nd nwtq wcF lo.d.d ilto thc w.[r 

ed dotodbBir wa *i.d out .a cd.1|!t rc!.gp 000\,) fq 90 6i 16, Thc g.l 

wD tsfdld 1o .thidim brcdid. (loorlll) sldion Dd dLoqcd to sLin for 3G 

60Didr6. TL. b$d! vw vi.!.liz.d on . W-Tm illMitdor .rd phologPhs *@ 

2ra Pollln r.tc Clrh lLdd.r (PrCl) 

T'lE PCR dploits tlc sllLgy of DNA rlplicdion to ddiry !p@6c DNA scqu.|B 

DNA dpliftoii@ @.G stE lh. DN PolyDae bitd! to Fitt6 o! lh. tinglc 

!!u(lcd DNA rdd& ud imdFr.t6 dorFiboou.lotid.tipho6ghdc (dNn, i o. 

srewils 5t ad .llo{i!8 ch!i! dot tid. H.oc., thq! is 6 dEPli6csion of th. DNA 

!.qu@ of ida!.l .nd thi. @r tr $b€.qually ddaLd uing AFo6c 8el 

Thc PdyDqe Chrin Rdrion (PCR) w Ffm.d to rryliry $. DRD2 8@' 

Pi$ . 

pair of p.iD6 9l:5'tCC TCC ACG C|cT GGC CAA GTT CIC TA'3' .d 5ltl4: 5' 

CCG TCC ACC CTT CCI GAG TGT CAT CA-3' (Nobl. .t d.' 1994) Tk priffi 

re u!.d !o DpUry . 3lobP nrgndt !p.$ing th€ pobdotlbic Tq I A 3it of t[. 

Dop@i@ D2 d.Plor @RD2) 8!ie. PCR coodilid w@ oltimit d eith 3l'sht 

Dodifcrliot in lhc m.thod to mplify th. geB e notion d b.low

Mart.i: OX 174 Ha€ UI Digest (Signa): 6Fl was dis$lvc

2,4.1 Corc.lhtior of Prils 

Thc primc pcrc prcha.d nom th€ Applicd BiGtBteG. 6Fl of lemritut d prim6 

w@ Ll6 al'd dibred in rhe rEtio of l:50. Opri€l ddliy wa L&4.1 260M. 

ConcoF.tion wa c.lcular€d wilh t!€ folloviry fomulal 

O.D.260 x Dilution t@1or x 33(O.D. I =33pdmt DNA oliepn!.1@1id6) 

=x ldnl 

=Y Sll 

Y/M,W-M (M.W.=bepaiBx330) 

M r l6+M 

2.4.2 Opddndiotr of PCR ordidolr: n. PCR .or.lido$ r.rc opdDlrrd udue 

Mrgr.rlum .!d t mp.i.trr. gr.dlc!r!, 

. M4!6|[m (Msclr) crrdle : 

PCR wd ceied out with diff€hl .oncdtratioM of Mgcl, dging 2.5 - 1.2 mM in 

ordd !o optidizc the mrdtrdion of Mgclr for nore aocifc bindiiS of prin6 10 

DNA avoiding nulripl. bads exlibiling rcn-speifc btuding d obwcd on agNs 

g.l. A sinSle d6i.€d bdd wd obscd d 1.5 niM MgCl, mdlration (Flglc l)- 

. T.Ep.nlrrc gr.didt: 

th. Lmpaatw eradi@l w6 als run io iind thc esl malirg Lnp@l@ of the 

pdne6 6 mullipl. bdds v@ obhi.rd at 52!C. Th€ gFdidi PCR ru with dif.€ul 

lanp.nlu. reging fbm 5? 6o'C showcd a sinSlc lad at 60"C {Figrr.- 2). 

2..L3 ArpllLrdo! ofDNA 

DNA dplilicstion *6 6i€d out h 20Fl @lion Eil'E 6itg appFxirn Lly 200 ng 

of goomicDNA(10!sro500ng). 0.2t!Mof o.bpri@,0.2 UTa4DNApdyn6e 

(5 uilgml) (Eppddo.ft), 200!M ofe&h ofthe fou rlNP!, 1.5 riM Msclr md 2 Fl 

of lhc rccomdded bufier previdcd by thc Muretur€r (Eppeldo.fo ws addcd p€r 

E&lion. IlEmo{}tlins w6.died oui on u Eppendoril th€mat cycld. Anq m 

initial dcn rudion a1 94'C for 3 ninutcs, thc DNA ws a@lified in thrcc !t p ctrl6:

2.5 2.0 l_75 1.5 t.2 

IbuE 1 M.s6iu (MgCL) gtldi.rd (2-5 - 1.2 EM) i3 

utcd for opliDizirg PCR @diriod rjc 1 5, FFelt 

310 b9 PCR FodEt oflt. $f!ia!6raic pdiars, A sii€lc 

dong b@d at IjoM Mgcll @@ndid ntisa 

3p.cific oElins, Lo. 6 dr,rios axl74 H.e lll digest, 

28

tuqliDs TdFtnfr (dc) 

52r 54.C 56t 58r 6fC 62qc iDxl74 

AErrc 2 TmpditE gndicnt (52{2.C) for optinizing 

rcR @ndilid. tlb Epi!!.da 310 hp PCR Fod!.t of 

lh -\i-dr6ic tstials. A siDeh sorg t{d d 60eC 

EF€a.lb. atElirg l@Ddde r!.d fd PCR @lFis 

Le. E 6ni.iB exl74 l|r. lll dis$r 

29

. D$anndon ar %rc ror 30 i@nds I 

. Ad.al,ns ar 6cPc ror J0 *cotuLs ! 15crleg 

I 

. ExreBion d 7?C for 60 s@rds J 

Ancr 35 .rles, orc DNA wa gird a lDal cxretrid 3t.p at 72.C for 7 nin!l6, A bla.] 

w h oul DN-A" w4 p@6ed aor *h @ciion arus wit! tne sople. 

2.4.4 G.l EL.copho6n! of PCR Prcdo.tr 

the sd€ pnceduc wo cdicd our s d.!.ribed in $ction 23.3. 

2.5 T.q I Dig6lion oa PCR Prod!.c by R6tdcdo! FEgtunt rfldl 

PolyEorpbbm(RFLPt) 

RdEiclid Fngmot taglh Polrdo+hin (RFLP s) is a tcchnique lhat r.?llMls a 

s!(ific molsul& tEtd on rh€ bsis of dilT€mti.l hldddizalion of DNA fragndts in 

a smp). of r€srricrion eMyne dig€sl€d DNA. The leDgrns of p.nicule rstiction 

fi.gndll ould bc helpful in pnvidilg infodalion .tDlx polyno+ni@ (inhdiled 

diII€Mes) EpHmt n by iG all€16 m.y bc honozygpu or nelmzygou- 

Sepl.r th't nad a good leld oa PCR prducl s d€tmined by cl€chophorcsis w€r€ 

diSdl€d aith ll)c ctictio ayme Taq I (r@ition squace 51TCGA-3). 51 0 Fl of 

PCR prcd@t solution vE diSsted wirh 4,5 U of T.q I dzyrnc (9 uirs/Fl) in a 15 Fl 

r@tion mixluc phich als mlained 1.5 d of rox r€..tion bufler providc! by Ih. 

MurenE (Mar Fmql!r). 

2.5.1 Gel El€clrcplor€rir ofDlg€sr.d DNA 

The se pmcd@ q6 cdied out d d*{ib.d ir stior tjl dc€lr th.t 2.59 of 

aSmso w6 u.d iGlead of 28. 

t.tt G.lolyphg 

Individlals w@ edotlFd a A lAl, Al A2 or A2A2 bsen on lh. paltd of bdding s 

!@ and agdo& gel elsrrophor€sis. 

. AlAl - sinel. bld or 3l0bp 

. AlA2 - firee bdds al 310,180,130bp 

. A2A2 .tmbed!.1t80dd t30bp.

2.5.3 Srlrt.ticlt rdysis 

The f.cqu.ncio of DRD2 s.ne Taql A a etc w@ 

(haropcndor,rca,cd ehibph*," 

",,"",., ",.-0,""*'"'Jo#J:1"'n j:J; 

nomar $ins chi-sq@ (x2) 

'ndividuals) Soodnes-of-ft rc!l. lo t6t rho didribllion tor 

deviation fmn H.rdt-WeirbdS Euitibd@. Iis is u@ @ oemonstr.r. the hrloth*is 

lhal two co dohi@r auto$mal allel6, in this casc At md A2, is the mosi likely gcneric 

tn@ry to dplain iI. th@ piqoq?6 (AtAl, AIAZ dd A2A2) Gi in $6c two 

c@rrnml greups, Ditrsftccs in ctinical ch@t.lislics bctwco lh€ t&e groups of 

gcnortTcs ih lhc plticDc wcrc urotr?r{t by urcofrlodorl,s r-rcsl orI? l$l, 

The Hardy-W€inbcrS principtc $ai6 rha! rh. g€notDic lilqu.Ici6 fo. a gde *irh lwo 

diffeEni slletd ar€ a bjnonial tundion of rhe alcti. trqucroq (wcavcr and lh,tdck, 

lDl). ll|hc At tctc fn{udcy is n?rc$nrcd by D, ano urc 42 a ctc trquoncy is 

Ep6cnrcd by q, lh.n lh€ expe&d nunbr for c&h phdolrp€ is 6 follows: 

AlAl - p2tr; AlAt _ 2pqn; A2A2 _ q2. 

whft n i! the lolat numb., of al€res. 

2JJ.r t: (Cti:) a€dtg !.hg r t c @!d!!ecy r.bt6 

The CniI rdr urg onrineocy rab,a s.! ccd ro compd orneEnc.! rn pnqolrle 

oshbur'or, dletepEeattu4 lrd allete 6q@ci6 b

\vl!@ R is fi€ ror:! of fie rew th. cell is il! C is lhe total of tE @llm tne ccll k in' dd 

T is rhe 3um of all..lb Thc d€gc of fr!.dd is tha ldtq of res ninu on€ tirc 

the nunbcr of @lum6 m'nu onc: 

dr=G-D(el) 

Sic only one polForphis (Iaql A DRD2) ws studr'd, cor€ction &cordrg 10 

Bdfmni ws not contidd€d ne6sary dd thu! lh@ ws no re@plin8 of the sMc 

2,6 DNA Sequ.lcllt or ihe Anplilied Prodn.t 

The DNA 6.qud.c info@arion @ h. ulcd ro &.lvz€ mutarios a chdge in a 

paniculd gme *qlence thal nay c se d$de 

Brieoy ile DNA synftdis is inilialeil by uing a prima lhal dcllmirc lllc startins point 

of tne seq@cc b.ins read. dd lh. direrion of $c *qu@'ng @llon 

Didoxyrucl€otide! (ddNTP) (laleled wilh 0uo66t dv€s) were used in no6l oflhe 

s€qu@in8 rurioB b srop DNA sy n6is al tpeific nncl6tid6 Thc fr,Emmrs de 

sep@t d by loSllt fotu longdt to shond wilh a di{Idtue of onc nuclcotid. pnviding 

Eeh of thc fou did@xvnucloti.lcs 

Bood lelution a1 tiic €d of ihc imubatio! Peiod 

lluollgn@ a difimr color whd ilMinal€d by a lM b@n and e olomlt|c s.@€r 

pbvidG a pnntolt of th€ eqlence, 

Ihe s.qucncing ofDNA E cdiqi out by lo-l5Fl ofpuified PCR prcdat (song/pl) in 

l.5nl nico cdt ifusB nrbc, lOFl of ptiD6 with conHlr|lion of5 pnoldFl (5uM) 

brsd on five spl6, inc@ of l0 p6ole ceh lin. the F&lio$ @ incr4ed Primer 

Td suihuc for M&Dgd sdicc is 5O-58'C. Scqu@cirg @nd@t€d uldd BigDltTM 

tmi6lor cycling condilions de r€et€d Prcdncls puified uing elhsol PFipilation 

ed M sing Aulomatic Scqlencd 37l0xl. Abi lil€ (€l@koph@8rD, mw dar.) 

cEjr€d .ltd 37l0xl @D9l€1es dalysis.

2.74!IM!_$IqDIE! 

All ainal sludi6 wft p.rfomcd in Mordnncc wilh rhc auidctna tor rtr 

Exp€rimdtal Aninat ecepr.d by lhe Erhical Comfrilteeoffic UnivcEny ofKarehi. 

t.?,1 Elpcrimcra.l Alimt, 

M.lc Albino Spnsuc Dawley Bls wilh averagc weighr regms rrch l?5-2j0a wcrc 

housd 5 pcr crac nnd kcpt undc. sr,ndndiz_.al tctrrnmturu nnd trgrnints condirioN wnh 

rre. acce$ ro srddatd diel ed watei AI drugs were adninnlercd wi$ inrmscule 

(YM) injetioB for 2l - cd@uriv. da'r. The ainals wca ocaprt t€d aier l@m€nr 

Thc nrs wcrc dividct inb fivc 8btrtls tor ucilnEnt wrth lrrc inlipsy.lnric dnrg 

(l'ulopuidol u cloapiDc) s d$cribc pEviousty (W6 ct J., 2004;2006). Anjmat! 

w€rc tErrql chrcnicatr, for 2l &ys by injerinc inrnmeutdy natoFddol (0.2 mg/K8). 

co|)nncrcully avdlubtc iqc{ljor (ScEnlcc) l.ron Scartc or n uro roaD ol.! etutioi 

prqdq, lom r puriticd pbdud from Signa, Simitr,y, an@M wrc arrc tek{ 

chonjcally fof 2l dars by iijc{rins lhem inr@us.utdty wirh clozapine (20 nB/ kg), 

cilhq in $c foh ofstlrion nadc ftum comcEialty .varrabte r.btd (Clozail) fom 

Novanis or a eturion piepded from $c punred producl fron Signa. Conlbt dinats 

werc inieled iftrneul2rly qilh sdire for a simits dur.rion (21 dayr. 

2.8.1 Drlg pEpt.rtio! 

. Halopgidol (Sisn.) (tons) ws distverr in maninat moud (roFtlorstmrat rc c 

ac'd dd 500!l ofd.iotrt.{t ward, vonqed ed the volum€,s nade up b 5ohl 

withdeioniz.dwarcrroobr.inn@nccnrarionor0.2Dg/nnol{,nrs.(Ron,tdt9e4). 

. H.lopqidol inj*rion (sdl.) 5 nBhl *a ditucd v,th deron,zod wars up lo 2j nl 

ro obldn a @eent arion oto,2 mg/nt otdrug. 

. Clozapine (si8na) (toohs) wa diserv€d in nininal ahounr (4q0 ofHct and 

sff)Fl of dcionircd w r, vodcxcd rtrd rtrc votunrc wN nkrc up lo 20,nt wnh 

dcjonized wat r to obraid s @ncarstion ot 5 nghl of dru€ ud pH 5,6-6 was 

adjurred wiih toN NaOE. @F, t90}

. clozapin€ (Novank) bblcr ws initi.Iy $aked in minimat mounr (4opl) ofHCl 

dd rho 5 nl oldeio zcd warde6.rlded, vonded ed the nnal vothe ws made up 

to 20rhl with dcionted wsrq ro obhin a @Mnrration of5 ng/hl ordrug. The pH J.G6 

wG .djusr.d wnh toN NaOH. 

2,3.2 Colleriotr of 3.hplB 

Thc iats weE dccapitr&d on 22nd day an€r l8h or$e Usl irrjcction Thc btood 6dDrplcs 

wq€ rat6 in cl@ tubG wilh or wilhoul a{dcd and@asuret lor drftbrcnr 6ri.rcrions. 

Sem lnd plaha.dptes wer€ coll4rcd s.paElely and sror€d rr 20 "C. Thc bmins 

we@ rcoovcd wahed wird @td salinc dd Eaionally dislcd ov€r ctushed ic.. The 

sepls were slored i, liqlid dt@8q ai _70.C till ndh.r darysrs. rhe liver smpts 

wft .le w6hed wirh cold salinc ard stor€d ar -2OoC udilt tuihcr eat'sis. 

2.9.1 Dcrerminorton ,f 

of ot.l Probins by BCA Ktt M€drod 

Th€ brrl pbrcin concenhrion lor cach prcp.Etion wG dcremincd by rhc njco-ncthod 

of Bicinconihic lcid (BCA) pbrcin 6sy (Pic.cc, Rocttord, lL) usiis boviic *rnr 

. Bkinconimrc Acid (BCA) poleir Alsay l

p€rfomed in a BioRad MiIi-PROTEAN ll Dual Slab G€l cpPdtus (70hn x 80nn x 

l.omn) dcordins to lh. pr@dw of rnemlli (1970) 

. MonomE Solutio (30% acryl mid6 / 0.8% Bis-a.ylmide): 309 .fyl nide dd 

O.8g bk-acryhsndc wm dislved in distill.d watd ald th. volm€ w6 nade nP !o 

I OOnl. The solution so lillded dd sloEd in a dart botl€ at 4'C 

. R@io8 C€l Bufid: (l-sM rn$Ect) pH 8.8: 36.39 Triz@ b6e wa dislvcd in 

dislill.d wara. pH ws .rljust d ro 8.8 wior HCI dd the volme wa n de up lo 

. Slekinc cel B!fier (0.5M Tris-Cl) pH 6.8: 39 Trima bsc {.s disoleed in dislilled 

wat€r. pH ws adjulcd ro 6.8 witlt Ecl md ile volmc ws badc up to 50n1. 

. sodiumJo.Lcylsulfa,le (SDs) (10%): 108 SDs wa disolved i. dillilhn wabr sd 

the vollnc wa nade up 10 t00nl. 

. Amonim pq slfalc (APs) (lr6h) (2one/ml): 0.06s amoniu pa sulrare w6 

dislved in 3-0ml dislillcd vals. 

! N. N, N', N', telru-nethylerhylclhyl€nc-dimine (IEMED): Uscd d p!rchased. 

. Smple Diluting Bufld (0.125M Tns{l tH 6,8, 4% SDS,ztYA eltrnl le/.2m@ap1@llt@l): 

2.5n1 Tris (pH 8-8),4m1SDS (107t,2nlglr!.ol dd lol2 

nflaplo.[tdol w€re dissolvcd dd th€ vol@e ws rudc up lo l0ml with dislilled 

walq. Aliquor.s w6 stored al -20oc, 

. Elatode Tatrk Bulld r 4 (0.025M Tris pH 8.1, 0- l92M glycirc, 0.1% SDS): 

l2g Tris, 57.69 gly.ioe ed 4onl SDS (10"/") w€rc disslvad dd ihe volMe ws tud€ 

up to I lit€r with disrillet wats. The bu{Lr va dilut€d wilh dislilled wald ( I :4 bcfo.e 

. sraininc $lurio! (0.025%): 

2-prcp4ol 250 nl, Slcid &enc &id 150 frl dd comdsie brillidt blue 0.259 w@ 

dislvcd in I lit-ofdislill.d waar. 

. D€-stinin8 dolulion (loPl.): 

75 nl of Blrcial ecti. eid ed 25 6l of .thml w@ dissolv€d in l-tiler of distilled

El€tmphoBis ws cdicd ou on I Oyo .cpmling Sels lr.ee nr running get buner, O.I 9 

Dl I0p,4 SDS,3.33 mt di.liltcd wab,6,66 nl monohr Dlut,oh, 0,79 ntApS,5.99 nl 

TEMED) and 4% slekins aels (0.7s mtslekins Bctburc,, 0.06 mt l0{,4 SDS.4 j5 ml 

disrilled*rt€ri 0.83 hl nonon.rsoturion,0,25 nt ApS,2.5 ml TEMED), 

Egual domc or sdpl€ md smpt. dituing bulld in lh. Bro or | | I in a 6oilinS wate! 

balh for 3 minul6. ElerEphoGis was pcfom.d usin! crerRtc r kb(tfrrt.onsrnnr 

voltrsc ot 9ov/ptar for .ppuinarcly 40 ninulq ar uar (h€ lle dre had nig.aroi 

95% ol $e get l€ngrh. Aft€r staining rh€ gel wilh coomas,€ brue dye, bnnds werc 

analr,ql usi.s e!{liry Onc sonwrrc (BioRlt). 

2.10 trigh p.rtornance Liqltd Chronarogrrphy (FPLC) 

High p€fona.ce liquid cnoh.tography is onc ofihe mo$ wdcty apptied dalyicat 

sepaolDn lehriquc, D which rh€ cohpondrs ofthe unknown nixrurcs plescnt in a 

hobilc phe &. scp@r.d. udcr h,ah pBsuc by s .kh8,nro a cotudnconrrrnrng fie 

lrar'onary phas.. Th. @hponars f.vel ar di{Icqr 6t6 a 

cx,,, dirce'-,," r," ;,;.;:;;";;;"ru;;.ff"ff'il,;: 

nGuftnqk of lhe cumntrsuttiig f@n oridatiodedlcrron rcedon of6€ anat,,rc ar 

a surlablc.t@lrod€. sincc rhc lcvct otrhc cuncnt is dncclty proponionat lo rhc ,natyc 

coicolation, tisdcl€ror ws u*d torquantifi carion. 

ItPl-C, ECt) (AnlN-tcydo tiquid chmDdotsruph systcnu was uso( b dcrcnnirc lhc 

::::i': " bios€nic &rh6, noEpin.prdn€ (NE), dopeine {DA) dd 5. 

(5-r0 qd 

,:::ll-r-'" 

th.n ndalolire, dihyoo,y ph€nyl ac.ric .cid 

(DoFAC), honoval.nc &id (HvA) dd 5-hrdDxindolcia$c&id (5-HrAA) in concx, 

snaruh, h'd bkin, h)?othalds dd hippocMpus of 

r@lrndl othalop.ridot {d cloapine. 

bra'n tnq aptrcp'iale 

Exrecion mediuh: 0,372g EDTA, 0,02g Na mera-bisutl 

c'oic ftid wce d so,; in,,";,;il";il,'J:,:i::,:':,*f:i:; 

l00ml. 0.17o clsr.iD ws add.d s p@tuarie. ed s{or.d ar 4.c.

. Mobil€ ph&.: 0.05g EDTA 0.2339 Octe€ Sllhnic acid (OSA), dd 15,6g 

NaH,lOa ws€ disolved in l50mt of mcth&ol dd pH adjusr€d b 2.9 vith 

onnopho+horic &id. Th. mobilc ph4. M degased vith heUuft b.fo@ e. 

. Slldard pr@dtior Al1 siardds (5-rn, DA, NE, 5-HIAA od DOPAC) w@ 

pr@s€d by mating elurion of 0,028/20n1 of ceh stdddd excett EVA qith a 

cm.nhation of I ng/nl. 

. Slsd{d milturcr 10trl of e&h sla.dard .xc.pl IwA (5tl) wd r.k6 sd wft 

added lo 5ml ofdeio.iz€d ward. 

. Srald.rds ced for cslibmtion 

. NE - 200n8/ol 

. DO?AC = 100n9/ml 

.5-HIAA-100n8/nl 

The bnb dssu* wft exciied ed diered inro ddircd rcgio.s inne

t 

€ 

ItEt c.firFi- CEG hrifurhar Ib an @d 

tDd &r lb. Fr|t-ilon ofNE b Zhglbl DOPAC h lfrrs/Dt, DA 

lt 162!8/b! 5.IlrAA ir lcrhg,bl, EVA L 50ns/ol .!d j-llr tr 

3E

2.11 Esdnrrio! of tryptophrn h Boi! !d Llv.r Tksua by sP.ctrclluo.oD.tri. 

ft. Sperro0@ooeiric dalysis iovolv6 |he n6umel of mitt€d Edialion fiob 

qcit d alotu o. nolsll€s when thcy daay to th€ir Sroud sr.tes Th€ fluo@dce h 

d.tere

Foi stddd&, 0.02, 0.04, 0.06, 0.08 ed 0.1 6l of wo*ine sraldard elution of 

t)?ioph& wqe t ko in lhc &w-c.pp.d tub6.Icc.@ld TCA (lo'lt ws added 10 eeh 

1ub€, 0,2n1 of fomaldchyd€ md 0.lnl of f.ClJ ragdt w6 addcd, th. tubc contcnt wa 

imcdiatcly slDld viloou.ly on vortcx ed irdf.r.d io l!. boiling w.tq balh Md 

q6 @ol€d at Mn tdpdl4. I1t volun. v6 mad. !p to 4Dl wnn loe/'TcA. 

FluoFwrce wa m@wd at chnsion I of 4E0@ lrd .xcitation I of 365m by 

JASCO ilemn€rd (Itr.ca). 

2.1, E dudo! oa T.yprop!.! Py.oLr. a.ltvity h llv.r by (ry 

SFcr@phororetrk.!.lyt& 

Q!&fratv. Sp€rrophotom.{ry is !s.d s a p..dictivc lool lo 6c.ec iit@i1y of ligbt 

s a fiinction of lhc color, or mo& 3p€ifically, lh. wawldgh of figh $at pNB 

thmugh . slulion. IlE 3ign.l i. proponiorut to ltE doul olUelll which origi.ally 

slrEk rlE Dhororuh. &d is rhue s &cur. h6!@@1of lhc amul of lighl, which 

ha hd Fljmincd by rhc so!l. rhrcugh phorodiod6 d.rdbr 

flE W SpetbpnoroneLic &.ly5is wa u.d to me@ |ijc -riviry of r.tdophd 

ptmle in livq lise hoDoSq.tls by Fduing lb. fomarion of t t)4.u@i!. 6m 

t-irtyophd d ww ldgrh (1, nd) 365m K'&l@in. de ratios \J@ ctl@laLd, 

plon d asriilr dnc &d ciz}m edvity I crlcul.t d a tmol ot kyD.uMiE Inlg of 

tise filn dc slope. (Feig.lson !d Gre,rgrrd M.lM (l %l )). 

. Mdrphosphodc &id (lsyt 15I ofmhphosphoric &id ws dislv.d in loolt oa 

. PhcPh'lc bufld (0,2M, pH"?) 

Solurior A: 13.89 ofdi-htdrc86 phosphat w$ dislved in 500b1 ofdoo ztd 

Solution Br l4,l9e of dlsodiM hrdbgcn pncAhllc w6 di$olv.d in 500m1 of 

d€ionizcd wstcr.?8nl of $lution A ed l22ml of sol$on B w@ nircd ed lhc 

volme ws hade up lo 400rDl with d.ioniz.d wata- 

L-trypbpnm (0-005M): 0.519 iryptophd wa disslvcd in o.lN NH,|oH dd volMe 

q6 nad€ !p ro 500n1.

t20 

r00 

80 

60 

44 

20 

0 

l0 20 l0 

Ceenradon (mol.{tr'l) 

Filc a Srdd.d .1re fd TryFop&dn

. (Cl (0.51v0: 18.6258 KCI ws dlsolv€d in 500 nl ofdeiodzed watq, 

. NaOH (l M): ,loc of Naolt w.re dislvcd ir dcioniz.d wald ed volun. w4 m.dc 

. HomoSdale $lution: ?ont of KCI {6 Dixed {ith 0.5n1 ofNaOH md dr€ volm. 

ws rudc LD to 250n1 wirh |n. deioniz.d *.rer- 

. Subslraro solltion: l5nl of phosph.te bufir (PE A ws .dd€d to 30nl or lh€ 

rr?roph.n $l io. .d incubaLd ar 3IC p.ior ro ih. addirion ofuE homos€nar.. 

2.12,1St Ed.rd md€ of Lyn.lr.rb€ 

Slddatd cw€ for t lylclMie sulfrte *4 ohrain€d !o 6!d out rhe onMlratj@d of 

ktroEdne io ii$ue 3@ples. 

. Sroct stardard of Lkynoreninc sllfal. (O oolM)r 0 3063g of LlFdrcoine sulfalc 

m djslv.d in I N NaoE ed volmc wd madc up to loooml 

. Wo*ing sld.tdd of Ltt!.utdine sulfat€ (IO2FM): (] 00lM stoct sLndard sa 

!.12.2 Abrorpilon tP*tr. of Lkymtrrcn|!. srlftt 

Absrpriotr spelra fm I O, 50 ad IOOFM etution of LtFsMinc w@ Eko ar 250M 

to 5o0M ed the ndimm abetption (1 nw) @ ob$fted st 365m (FlguFs) 

O.0l, O.Ol2t, O.O25,0 05 ed O lml ofqo.tiog standdd w@ lald in spa61e lnbes ed 

wlme wd natt€ uP ro lnl with NaOE 8ivi.8 tne @mdt"lios of l0' | 2 5' 25' 50 and 

l0O mM BPcctiv€ly Their ablorPlion !g.in$ lml N.OH Mi laken al I md of365m 

dd rtrDd.rd cwe va Pron.d. 

2,12.3 S.npL Pr.P.r.rior 

. ftcpdlion oI lis homogcn l€r 6g of frcsh liva tisue wd6 homog'oied in 40nl 

of honoScnat€ $lution al CPC lor I Dinuic 

. Prcp@rioo of leiio! nixim: 15nl of tivd hohogdal' elulion wd incubat'd 

wirh 45 nn of tub6tzrc etulion at 37C silh @ttul shalina 080 

oscillaliotu/nilul€).

.S o. 

? 

|5t) 350 450 

wt',! L.ogI (m) 

n!.|! ! Atdtt 30.d.dr\tDraiD (i5c5{b}. 

/a

2.12.4 ltltlmollon ot eDyme .c(vily 

Thc tuync &tiviry q6 D6!Gd a1 orc linc int Nat of t5 minurB @8ing frcm 0 ro 

120 ftinuls. For thit 3hl ofrc&tion mixl!& ws t*an our 6d 2ml of h.hphorphoric 

&'d wad .dde4 sh.td for 5 6inul6 and tilreEd. I _5nr of NaOH wa addcd b 2.5nt ot 

6lt!e rn

Dnbtir elnlion: 200 ng of pd.siM fenicydide (K3 Fc{N6), 50 ng or potassiM 

claid. (KCtt &d lr|o ng of pottsim dihydmSd phoQhalc arh)dnu (KI!, lO.) 

w@ dirslved in dislilled w.lq dd ih€ volMe wa mad. up to I lila 

Th6 @m@iatly p4?r.d stct si{dardr for hdoglobin (B@bringd M@ncin) wnn 

lhe €om.otation of l5m8/dl wd u*d 6 putchscd. Thc skldards wcF pEparcd m 

sdi6 of di{fqal cotu€nttarioG (2msldl, 6 ng/dl' 9 ng/dl {d l2 mg/dl) win Dnbkin\ 

slution ald ln. volwe w$ rdc up lo 5 nl. Tbe t!b6 q@ lhorushlv mir€d dd Ead 

.t 546 m (Micto lab, M€rck)- The calibtttron cwe wd Plolt€d (Flg!G6) dd fi€ 

@nMtlalior of hcmoglobin v6 Epllgtcd 4 ydl 

molc blood (2otrl) w4 t.I€n in lh€ sdple tuh's to vhi'n Dnbkin's $luno' {a3 

added sil bixcd lhmuShlv. All lhe tlbd sd incubalcd for 5 mmut6 rl ltm 

rdpdlw &d ab$rbdc. wd iedu€d at 546m 

2.13.3 Eidudon ofTot l R.d Bl@d c.ll (RBc) 

The INbd ofrcd blood c.lls es. calcdarqd dd ioponed d iI6 nuhb'r of td "lls /nl 

ofwholc blod by sins h@oc}'toncta (Ralh&I, 1983) 

. Ti$diu cilrale (!,8 d wd dissolv€d in 100 nl ofdisrillcd Natct 

EDTA tr4ted blod (2od) wd addcd in $ei. Gp€cdve tube (label'd) wilh tn$diun 

cib.re $lurior (Gd cell dilulin8 soluion) aid uomueblv dir'd- Tb' sple ss dihtcd 

to l:201. The diluted sPl€ ws pip€tre out md se'pcd into lhc RBc coNting chmb€r' 

daline !@ thd th@ *@ no air bubbl6 .td @ ov'r filing b"ond th' ndrcd a@ 

Thc ch66a es bn on th€ bdch for I ninutes' 50 thsl c'U corld get s€ttled in lh' 

outitrg ea RBc wa @ut€d udd hjgh-pow'Fd dry l@s (Ni&o'! Ja!4)

lo. 

I 

?0. 

a 

21 A 810 12 

c.didofflbG'eI) 

ftr. 6 Sa.dd ott! oflhgbriL 

46

Nmbd or RBCS (millio cu.m) - N!!rbs-9&!d jEU!-celqdr dllulen 

Afta .out x Depth ol tnc nuid 

W!@, Ar x DrDi! = Volmc of rhe fluid in ihc emtiru chube. 

A16 Coutcd = 5 x 0.04(0.2 x 0.2 = 0.0a cu. m.) 

D.?rh oflh. fluid - 0.1 m 

AB x D€plh = Volme = 0.2 x 0.1 = 0.02 mD or nl, 

2.13.4 Eitlddlotr ofP.cLd c.ilvoldn (fcvl 

Th€ blmd I Lto in rhe sc.lcd h@diniz.d capintry tub€ .nd mEifugcd. The volM€ 

of p&k€d rcd cclts ad thc p.lqiaee of ih. whote bl@d (l€v€l of pl@.) w@ 

d.hined by a hmtocril rcad{ (R.ph&I, l98l). 

H?dinized capilhy tub6 w.r. u6ol 

Thc capilldy tob6 w@ fillcd tii! blood smple Ore.nd 6f the tubt *6 ealsd &d 

cdLituged (mi.toherubcnt mhitug€, Gemev) for 5 himtes' The sedime ed td 

c.lk / p&!.d r.n ccls volm€ wd nolcd with lh. h.lP of h4'locrit card r€adcr' 

2.13.5 EldDrtlo! of b.E.rolo€tc.l i!.ttd rnd CBC bv Altotut d C.ll Codt'r 

. PbGph.tc buficred Salin pH ?.4: KHTPOa ard N.'HPO, @h 0.1% dd pH wd 

adjulad boforc 6n l vdue of0.85% wilh NaCl- 

Thc EDTA-d0oasuhr€d blood smpl6 w* !5ed for lhe ell @ul€r' 10 ml of 

plDsphate bufcttd s6line pH 7 4 rc ttlcn inlo b€ake6, ,4 and B cPetivelv 0 02 ml 

ofwhol€ bl@d ws added to the beakd A makins the dilution of rho blood to I :500' 0 I 

ml of diht d 54ple *d rato &d wd addcd to beld B, with dilorion oI l: 50,000

Th. €e[ coutd Ema Pc 604 detmin d 6ve pamclc6 i.e. henoglobin, lolal RBc 

@ul RDW, PCv sd total \YBC cout 

2,1!.6 DrdDdor ol AbelnL hdlcs 

Tt. Abelok hdics (MCv, MCE ad MCHC) w.r€ estimat d bv $ing sttnddd 

fo@ula im hdoSlobia toLl rEd 6l@d ccll E3C) 6ut Dd p&k d a[ volmc 

(?C\,) (tuphlcl, 1983; Silmos, 1980). 

,.13.7 lrc! PrcfiL 

Stu irc4 total i6n binding cap&ny GlaC), elu F€rititr ed % lrsf'din 

$l!.lrid v@ |rre!s.d fd iFn pm6l. dcl@tultion 

2l!.7.1D.t rmio lotroflrcn 

Ion wd dddined by deprcrciniztion hcthod uina cobnic GdibH tn (F 10r) Th' 

irdsfmin!.bomd i6n is Fldcd bv Sreidin. htdmchloridc ed foms ! @lolcd 

complq by rcdei!8 it b leII-ioE. Tne @bred @nplcx is highlv s?eilic due ro IcU_ 

ioro {oFfitltion ofrh€ smtl.. (Adis c! .1 . 1981 ; Slookcv . 1979; Ldbcr 1980)' 

. R€ag.nl 1 G@idit€ hldr@hlotide 4.5Fo1,4 buffcr pH 4 5 

. Ragdt 2. (Color @gat) Fdde Jnisodim elt 5?n dokr'l 

. R€Sdt 3. A@rbic &id_N&salt 2 5S 

. Reas.nt 4.lron Glddad) 3omnovl- 

. Sdpldsnld.rrl blul €g6r dislv. escnl 3 (@rding lhc @out or 2 

spatula) i! 50 nl of@8€ni I 

. R*lion Entu.: The @lion niit@ ws prcp&ed bv addins lnl of Fsot 2 

into 25 nl of spusrand.td blank Mgot 

2OO Fl of eN {s mixed *ilh I ml of @lio. mjrtrc rd i'cubded for l0 oftlte al 

roon lemp.ralu€- The stand,rds weE lc.led simildlv For seple bldlq 200d of 

s4@ wG ctd &d I nn of d86t 2 ws add.4lhobusllv mix€d dd itrcubal€d for

10 mirut6 al room idpfrie. nE ab$6ece ea F.sued at 5?8 m agMsi in€ 

Th. stu iFn ws cdculrLd a folm: 

fnot4 = 6A dron @ple) xN Or pgldl= 106r x 6A(lonmplc) 

6A (siadad) 

6A (.b$b,e) - ^ (e,ryle)- A (sBLlA GaL) 

6A (!bd6.ne) - A (strd,rd! A Gtdtud bLnr)-A (RrL), 

N = t0 llfuvl (trocndid ot.llldtd) 

2.1!.7.2 D.t rDlMdor ofTot l Ircr Dbdbe clp.cltv (IIBC) 

Tord lror Binding Cap&ity GIBC) vd dct€roftd bv 6ing Cartonic CnbH kit 

(LlO3, Ml} TIBC w6 m€Gurcd aft€t satur.lion of lh. irNfnid bv m inn $lutior 

dd.derpiionof ln€qcsitonhyna8trsi@oa$on .(Stmkev1979) 

. Rog6t I : So(ualed Feclr lohtion 89 5!novl. 

. Rag612: M.endiD.dnonale (d dern6t) 

ll) M.lhod 

Rsg6l r (sOOd) ws add€d to lhe tuh. witn 250F1 of th€ *ru4 nircd dd in'ub'1€d 

fd 5 ninur6. To rhis I nduing s!@n ttag@t 2 (m+n6im cdtollre) wD adtLd' 

Thc tub€s w€re incubaled for 30 niou6 ai 2cr'c ed w@ cdhifuged al 3000 rpm for l0 

nirur6.Tn sup.6ara w6 lr€t.d s c@ dd ndured pith lnc Iton ldt (r l0l)- 

ftc &tivity ofTIBC it ttte s@n vs calculal€d s follows 

llnol,4 TIBC lobl = 57Ox 6A (S) Or ltg/dl=3183x 6,\ (S) , 

6a (s) =A (smpl.! A {sBL) 

2.1!.7J Determlmtiotr ofs.rud Fer.id! bv ELISA 

EEFel-inled tM@mlb61 Asv (EL!SA) is t wtui dd Pow'r6 

oelhod in

dlinaline nelDl to pelbr ordded Dat ri.b in the biolosic.l sasplG it d b. pqfom€d 

lo ddude €irh.r the p@€ of &rigd o. th€ pcfte of artiHy in a sdplc, 

Th. eftple wirh e unlnom dout of &tigB. h imobiliad on nift litd platc 6 a 

slid supporl sd rho rhe deletion etibody is added, foming a @npld wi! dE 

dtigd, The deleotion eribody ce bc @valently link€d ro e @ynq o. cs il@lfbe 

detsied by . sondrry etibod, which h linl.d to { @}me Lhbugh bioconjul,ttion, 

Atcr thc linal sah st@ the plale is dcvcloped by adding m dyDatic subslrrtc to 

p'od@ r visibb nglal wlich indicatB $e $dtily of dliga in the splc eilh.r by 

utlitng cnrcnosdic st6t-316 or Auoos.nic subrltdG hatte nuch hid!6 34ilivity. 

DRG disenGtic GnbH bt (EIAj872) *s us.d aor tbe detdmimtio! of$run fmiln'. 

.o9loin8 ELISA nedrd. In !4.d ion l4€h wre eiat€d wilh ircn dcficii vihl 

hcpalitis *he.. 6 deresed ldels w@ dleialed wi$ cnrcnic i.fections, n@hr6G €tc 

. Artibody-cod€d wells: Micb rild wclh @aled wirh nlbil dlibody-fc lin. 

. EMFe @njusate Bsol conLining moue monclonal dtibody aedirin 

@nju8.rcd to hoffidish pmxid.- 

. R.f@ce sland.rd set onlaining 0, 15, 80250,500 and 1000 ng/nl hllM livd o. 

splm fmitin in bovine sm with pcdativg. 

. TMB rcag€nl 3, 3 , 5, 5' t€tran.thylb.nzidine tiabilizen in bufid solution 

. Sbp elutio. lN HCI 

20,11 of sbrdrds, mpl6 and contbls speliv.ly w@ add€d inlo alPbpnrk wells. 

lootll of @ymc @njngat @8qt w6 ldded inb @n we[, gdily nix.d ld 30 

@ndr sd incubaral at mn ldprarw for 45 min 6. Tbe itulbarion mixlue wG 

rcmovcd by llicting well @nlols i!!o a suila!|. *6le cotrt incr; wells *crc rin*d 5 

tin6 with dklilled or d.ioniz.d war.r by slrikins the wells sh.rply oo absorb.nt papd 

for removal of Bidual waler dmplcls. l00tl TMB reae4t wa added into ceh p€ll 

g6tly mix.d fo.5 6*onrb ed i.cubdled 6t toon teDperrtu€ ir the dlrk for 20 dinules 

lo0rrl of stop r@cBnr e6 added inro oDh well dd smlly mixed for 5 sondg. The

oldc.l ddy (O) of& .qf- d aodrf ir.. @!d d 45tb rtlh. ni.{o 

liE rdl ft.d- ri6ir 15 DirE fi. rd!,ny of hilb i! e xlm .4 rI 

€bldtrDLdiiarnhd@c 

,.r+7r lt.di. llr.lr'l 8.btb ('.Ic) 

IbX.te Iffifi Se.doo 06T8) r. c.Ldd !y tt! ftdlh, 

%TS - S..un itldnDc '100

RESULTS

3. RESULTS 

a.l Aldp.t.todc Dr{!|r a!.tr Std. E t .l| fid PANSS 

It hs lur{ hfi tlctrxlBtrrtot th ttr rrtipi}tt|'||i( nn,l,"r {,tirt{ d,nt,. t.,,,?, ( 

ck$in.d on fi. b$is of rh.n cffic&y in @t otling posiriv. .nd ncg.tiv. syrnplons of 

i.hizlphmi.. In rhis srid e! Epon . d.finic @m@rualiztjon nccdcd lo bc 

!ddB$|. i'r o.rlq to fir{ {n eiulion bcl*ei UE {nlil,sr.tdio ttru8s, $cn iidc 

.fier Drefl. ed rh. P^ltss 

Thc @bi.@8n9hic .rd ctinic.l f..r@ of l2O *hj4ph@ic pltial| chrcni..ly 

rElcd qi|h hrlop.idol {n=92) .Jd ctoapin. (n-28) w$ summdiz.d in t.bt. t_ No 

risninon| dilrmc ws ot dcd in rhc tw trcr|nor sDurt tor nlq os. 0r t,r onsr 

of illn*, durid of rarmdr.!d d6rg. of eri!tr lhoric dtug rqrlMt, SiSnitic&l 

(P

I.U. r Ddocivhic dd cliricd ftr!|n of &tiz.Pbdic paliots uEt d wilb 

brLpdidol (n=92) .trd doz4iE (!+8). 

A8e .t r oset of i!!.$ (}!d) 

Dunrio! oftidtndt (ye6) 

Dosgc orAP dNgs (ng/.Ly) 

lditiE stnpt 6 (94PS) 

N.Bdire 8)atoD' (7.NS) 

PANSS(%) 

0Lto!.tlio0 

29,01L9.05 

3.66+3.03 

22.30.E.39 

56,3?+8.26 

. PANSS, PositiE !.d N.*.tiF Syrpr.ro S

IrbL 2 CorbtioD Mly3b b.le..n PANSS &d othq oliricd pteelcB ofdD 

Schizophmic p.tidt8 taGd with hdopdidol (n+2) ed cl@pi@ (!-28). 

as. .l r od.t of ilnc| 6Es) 

Dmlid of dqtodt Oe.) 

Irca86 ofAP &W. (dgid!y) 

Pciriv. 'yryrd! (91iPS) 

NcsdiE .yotsmr (%Ns) 

H.lo!.rldol 

r- 0.26 ( ) 

r --0.013(D) 

r = -0.r0(D) 

.{.1?8(B) 

r-0.0?4a) 

.cmrrrin @!dr G) ('4.05).', (p4jolr.., d, 'r.r.is.in€d. 

' = -0.27(c) 

r{21s) 

r-0.0t(B) 

r - 0.026(s) 

. = -0.073(N)

T.bL 3 Coopdicon of6. sid. .rc.t pofiL r!€&i.Ld *ilh g?i6l (h.lopdidol) .!d 

atlic.l (cloaqie) eliFylhoti! dDg., 

EPS lilc 

(Dr!tori., PdriI|@is, 

Arltbid.! T&dire Dtskitr eir) 

. Th. 'Ei9 of .id. .ft6 & !q.*|t d tt .tfitot +/.- 

. rd.0fidol @oF2-2mo3/dry) 

. doah. @oG5AOE8/dy) 

X.Lp.rld.l Cl@pit.

Tdle 4 Diltibuiion chs&lertrics of PANSS ilds u*d lor lhe dissnosis of 

schtopbhia patidls lrdled wirh halopdidol (n=92) md cloz.pine (D=28). Th€ 

sybprom e PFql.d 4 Gp*tive pd.dlagc. 

Shorod 

PGitiv€ Svnptomr of Scbiro.hrdlt 

P,lrrcid d.lsioa, or &l[ioo ofFnanioa 

cGly dnFlloiz.d or abbic b.!'viq Il 

ii'rr'.pde b dc duttm d 3rinli. 

^fid uNU2l nsr b.hvi$ (!d!g, clli,s), 

&s!!!!.qgr&!l-clg!E!!rr4! 

Ar.si' (drnicur'y or tub ir b spajl) 

b4pbFfucirlt'j|ltg|rkotifut 

dasililyhsenl'4siudkp@pl? 

lnrbiury to friG iridnd. d t e Ftod:, 

DilEcdV qp'.sins rhogbb

poplo (100%), ad social isolarioi (lO0%) erc morc conmonty ob*ded in case ot 

halop€ridol(n=28)lr€al.d*hi@phrcnic p.ricn6. 

Eovev.r, the n gativ. s)mproms includin8 lsck of @otion (a5,45%), affetive 

flattnine (63.67%), alosia (54.54%), and sciat iehtion(90.9%), di&fsanized rhintinc 

(81.817t, difliculry in hddtandins (81.8%) and difficutty if, inresrating rhoushls, 

l|c1itr)+r ni bdnrviin (4545y,), rLr.o onrd |)tlrr]ro,t tr I,rti0|ts r,ert(t wirtl 

1.2 DRD2 gem polynorphkn h Scht@pftrcntcD,ttcnrs 

This stion deals *ilh ihe 6!@iation sudics bclwe. dlelic fiequaci€s ofTaq tA 

R.FLPt in $. DRD2 @c?!or 86c. Thi! B.no b larcd in lh. chomGond position 

llq 22-23 (Figur. t) &d rhc tuplcs trom ch@nics y Le.rld paticnrs ofhltoperidol 

ed crozopin. v.r.3ubjer.d ro pCR srudio, in ordcrtoddcnrinc rhclltcri. r.cqucNy 

dituibulion. The s€noq!. prih of dc 5d. lmrlc is .rso pwme{ hce. 

Caonic DNA witn rhc puiry of r.7 s damin.d by Spcchphoromcld w6 rur on 

,ge* g.l 0.8yo to chet it int.gity. t cgjty ofrhe DNA spb non $c blood of 

*hraphr€.ic palidrs ch@nicaly aqr.d wilh h.topr ot edor cloz.pinc. Single bad 

w& sen on |n. s.l thowin! int 8rily of$. DNA. 

d'e mplilicadon dd gootrling oflhc DNA w4 ffied our by using potymere Chain 

R@tion - R6triclion Fhldcnt Lcngrh potynophisnj (pCR-RFLp,s) r6hniqtr6wjrn a 

pa'r orpnmer 971 ed 5014, ro anptity a jro bp tragmenl sp.nnins lhe potyno.phic 

Taq I A sire of lh€ DRD2 gcne (Fig!rc S). nr€ 3 lobp dnplifi€d p,oducl (8Fl) of DRD2 

cene wN li^t M on r8es. sd {2%) ed vkualizcd usins elhidim benide srain. ,tE 

PCR bla.t *s ued s conhol. pCR rslhs of 2ol. agarese gd d€drphoEsG showed no 

bad in the conrol; ho*€v4, very proDincnt bed in rhe 310-bp @sion w6 se€n (figure 

9). This rcp€scnts d uncur iEsmcnl ofDNA, $e Ar llete. Two iEsmcnls of 130 bp 

and 180 bp Ep@at rhc A2 alt.lc whilc ibr.e fragmcn$ of3l0 bp, l30 bp and t80 bp 

rcrcscrl l/A2allclc(t{gurc t0& lt r_b). 

We ha!€ obswed rhar rwenryjevcn paticnrs wcrc honozygors tor the Al/Al a ctc, 52 

*crc hclcrozygous tor AUA2 ! qtc !|l(l 4t pllicrk wcr homozy8ous lor 2lA2 rlclc. 

HoNwer, in the lon-scnizopbrcnh individust! Gonftl) groups 5 weF bomozysous tbr 

A I aUele, l3 wer tui@zySous for A I /A2, &d 26 w.re homozy8o!! A2 (Trble 5). The

frl 

q t .!,,r 

'! j ,!q 1 1,! tr '1 

n r i{ in ia ni ! 

{1{lEtEitrtsrrrtr 

DRD2 GEI\'E 

I 

!; t ! !$t$t 

rtun 7 chs@@al lo..tio! of DRD2 gFe. The DRD2 g@ b locned od 

cbrcm@m. 11 !t posiiion a!!rcxin loly q22{23. 

,8

32621 agc{accacaaglggsseg 

12641 ttqtctsaat tlccatcicg gctccrggct t6gaaccaoc cagagtSigpc aclgaoggct 

32701 c.rrgc.cri 1d.gga Cgar, atgargcoor gcrilcggcr gcgeagggcc agtaScagge 

32?61 gtgtgcrgct cactccakx tggrcgt ca gctgggcgcr tgc!*gglcc agcacftg! 

32821 ggategctgt gtgcccttgagggcggccs ggtggcggg tgtccagccc acrtgrgc 

32881 gggcgtggac atttgcgtga rgttctakga ggr &arsac actcalsssc 

FiFE t ShIt@ of 3l0bp E8i@ oftbc DRD2 Ctu s!mi.8 rh. TlqlA sirq 

IE T.4lA rcltridioo sir€ is Eptqa&d by srdisr e) d @l@ti

{x174 

figrE 9 2% agtu gel of the rcR pftdEr dpfirying 3l0bp 

olDRD2 94. tjG 2 - 10, t2 6n ir rcR podu.r ton lO 

$hto!l'qi. Flidts reFtst d by r $rodg I | 0 bp b6nd re 

2-5 rpi.ars {r bdoDqidol raa.d polienrsj IrF C9 

Eprenrtdoapirc rEted pori.nB qhile l@ 10&12 EDt!$eil 

mmrl @tr!!k. l!. I I c@triB rh. 6ulrs of a bl&l rsrion 

wiIll no DNA, Lee I @nlai6 ih. 9X174 m|s'ne w.ight 

60

l|grF l0 RFLP'S of DRD2 delror goc sp@red on 

2.5% agNe gel, Lse! 1,2,+7 ed 11 Eprcsi DNA 

lion $hiapbmic AlA2 hcI!@ygo6 pdidts, hlving 

tr bdds. ldd 3, 8 {d 9 FFlst DNA im 

indivituli hdn@r€N for 42, nNirg tm t6nd! of ll0 

bp 8rd I E0 bp. rlE 13 Gplsn! OXI74 Ha. ttt diglsr

UryD 

t2 t 

r|tlt rr . nE die.qa.l pdar of '#rg"d 

/digci.d (uDD) silb Tql d|d Ft s Fc&Rru 

prldlc|. oo 2.t/a rg.rlc g.L @d !@b6 lrc 

rpr€ctr 3l0bp @lifild lrqtu t of DPj, i.l. '*fiI. 

ercn Mb.r l&q Eptlgt Taql diEEd€d prod!.1 of dF 

s.D indivi&ds dryinS .llclic pen Al, A2 rut 

52

UD'D 

345 

Ft E ll b, rhe djff@nid pdr.n of 'Ddig.r.d /di8ca.d 

ruryD) *it[ Tlql .!donEl€* FCR/R.FLP DrqlBl! un 

2,5% .grc Cel, Odd nMbq laG Rpllsr udiSclr.d 

mplifi.d producls etik eo rmbq llG eFrsr $.ir 

Fsp€.rive T.ql dig*led Fodlcts. lr'M gel show int ne 

h.rde of 3l0 bp EpEaning Al hmoTtgou $hiaphhic 

II 

r,5060 

63

T$L 5 Diltributio! of DRD2 smrr1. (F164) snd reLted pe&Ft F to Ta4 1A 

PolyEo.phi@ i! lh. h.lopaid,ol cloz{ilo ed control subj4&. 

Tiar€d (28) 

05 

2l 

06 

ll 

t2 

25 

3l 

!0 

. Cl'isq|nE (r, aoo(bo of 6r r,6! p4.05, 

o.26 

0.44 

0,43 

12 =8,55;p=0.425

gcnolyDc disribution ofTaq lA dopaninc D2 Bct'or gcnc otschi2lphrcnic prticnls 

(halopcridol ed cloz+ioc lrealcd) and nomd conrots weE in aco.dscc with Hrdy 

wqinbcrg equilibnm. The fiequocy oi Al auete difl6 sie.iticdrty b€rwea rhe 

*bizophr..ic paridb trsled wirh h.loperidol (0.44) dd cloz.pin. (0.41) a complEd 

wllh $eh nomal conftls (0.26) with x2- 8 55df=2, p= 0.425 (T.bt.5). The marked 

dill.Mc. in the all.lic ftequflcy ws obscNed in $e real,henl soups (haloDcndol ed 

cloapind eirh,(2 =2.5099,p= 0.285 s compsed 1o contml wilh 12 =6.047, p= 0 048 

'l[c Al rdlulu *N tbon to tt! eee,cinlql witl 5] (.t4,%) ot tlr Dt) kruwn 

shiapnrcnie,burwirhonly 12(10/tof{hcnon-$hiephmic@ rok. 

3,2,1 Scqucne ,r.lFir oa lhe lt Obn .DDIfl..l produ.r of DRD2 gcr( 

Th.3l0bp bdd on lh.2% ase* s.l t@n bbon spr6 of$hizophr.nic parienB on 

balopcridol sd cloapine trartncnt .Dd ftom rh. btood samplG ot contol subj*ts 

(rigurc 9) wcrc cxciscd {d analyzcd usinglO-t5!lotpurilcdpCRpGluct(50ng/,10. 

ScquencinS qu conduct.d undcr BigDy. lminabr crtine condition! ancr Erhanol 

PEipiidin ed M on Aulomadc Scqlcn@r 37joxl (Appli.d Biosyrrds). The 

s.quft. rDcl6 obsdld h b,lopdidol drd ct@pine Eatcd schiaphmic patidls e 

r5 .) cpe$vdy. 

shovn in (Flglr | 3 . - 

In ihe schiaphrcni. populalion invBigard, no significdr difa€rence wds aound in $e 

allclic frcqucncy bur DNA sequacc ealysis ofrhc 3l0bp Esio. of DRD2 shoved rhar 

all tchiz,phrcnic pdionls, chroricn|y lrc cd wilh hltoDcrdot or ctoznDilc. wcrc 

homozygous lor a C-.-T lrdsition in rh. base pan positio. 32827 .dying Ser36lc 

mutation (Figur. 8 & t2 , - b). Otrc otour impodtrr obsefraroN rs tx4r th,s c T 

muahn rs nol al$ialed wirh $c non-$hi&phmic conrrol grcup. Moevc.. the 

s.qudcc dalrsir slo*ed no si8lifie.r cft@ts on rrqrrdt our@n6. 

Ann scqu.nciry, the 6uus of jtobp mplitiqd prcduct of DRD2 s€i. of the 

$hizophEnjc p.rienh on halop.ddot / clo2apin. rrarrb€nl &d conrrct sahrls. *ere 

sbjcclel lo lhc bNh l@dl dienntq srrch toot (BI_AS1) to Inrd orl ,cgtons ot.tocul 

sinilaily betw€en *qumcs. The compadsor oi the nucl@loe sequcnces lo darabss 

and lhccalculatcd staristiql siSnificdrcc ofscqucn.e marh6 arc shown in tigure Il c 

& 15 c for thc hdopqidol uaLd paucnts s4qucne dl showi in Alurc t5 c aor $c 

cloz4n. let d *hiephrdic parjenr6. AddidoMly dle sre id6rid6 Md saps in

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plus/ninus str.nd ws als giv€n in th.s. figurca, 

Fisurc 13 d - 15

g 

500 

300 

2oo 

100 

o 

EAConrrcl@ H.ll @ HrlP-Clr.T :Ch-P 

F!!n 16, C@Fris of doFrfu lcEl in dif.t nl nt h.i! 

'!giN 

follosing ctrMic (21 cdgutiE

.3 

-rcon.6l E tkll @ ti.lP -c!.TE=Cb-P 

FtuF 16 b CoEFri$tr of doFEi* l4l in r.r 3tri.uD 

fouosins chEnic (21 onsccllivc &F) l/M trcttnqt of 

hslopcridot,rd cloapinq (ommcciully avdhblc l'lnj*rio,v -l: 

Talla !!d P- Putif.d fom) !!d contol spl6 

(rl0 *h pO.m5. Srdrtt t{!3) 

EI

6r.4%a2.93) in botb rh. qpqin@t t aoup! of cloz.pirc Eatl.nt E+etivdy 

(n8!n16r-b). 

Th. ld.l of mronin w$ 3ignifidtly ierc$.d in rhc nidbnin, hyDorhrtmls dd 

3tri.lm bd .lidtly der...d in thc @ncr (r.?,./.+26.9 .!d 6.99%arl.6) fo ow.d by 

tbc chrcnic t!.ttn6t ofh.lopaidot in borh.rp€imor.t gEups (@m.Ei.Iy Nritau. 

t Uct .rd in purifi.d powdco qperivdx d @np&d lo rh.r oa cont@t ors, Thc 

naimun imtt4 in thc &otooin corc.nrr.raon wG ob-rycd in lhc .xFrinqrrl greup 

tet d wirh puifi.d fo@ ofhatoFridot in a[ th@ rcgjoE: midbain (2.0%*23J). 

hypothalhu. (254.8%i2t.a) lnd in srillum (2228%+39.7). Motuvci rhc *mlonin 

@nantr.taon wq sisnificdtt, imra.cd tu nridbhi,r (8,t%{6.5) in o$ ot. rtrc 

cxtcrinEntrl soup r@d wnl comnErcialy NJitnblc hutqEidror nrjeriotr (fig!.c 

11). 

CorcuMt &ct!e su o0lcnrd in .ll rdos .ncr chrenic rrqrtndr of ctozjpire 

crc?t in conq wh6! $roronir con4nhrion wa! tnt.dly hctwld (3932%*2.01 

rld 23.0%t4.2) ...rqriv.ly in borh rh. dpaimdr g6up' Addilio!.lly in 

hyFthdour 5igilica de@r! (5a.65%i9.5) ws obFryGd in rh. cxFrimdr soup 

rMr.d wirh rhc pu.ifid fom ofclo?:pin Gigur.lE)..Itc varyiu crer of rh* dtuss 

on rcuD0_ulmi|lq nEy s@unl tor $c dirTcan@ in lhcjr ,ido cII*t ,,tlntc itr Btudsc 

Thc livq dhibitcl r sianifiofl inclt4 (p

I soo 

e 400 

E goo 

ElCo rel @ tr|-t dthlP 

-CL-T :Cb.P 

Fisle l? Comp.iis of 5-HT coMntdion in difr@l DEn 

r!si@ rollowins chmnic (21 @'rivc d.t!) UM oqlnd or 

hrloeqidol lrd cl@pirE, (@d||iwi.llt tvlil.bl. l-lnjeddv T- 

T6l.t .!d P- Puifi.d fod) !trd conEol @d.3 

(FlO.dl rd.00r, Sdbr.' i{!d) 

83

3.5 

3.0 

2.5 

2.O 

BrrinTrlploth.r Liv€.r'tvpropbtn 

[:c.nrrl @ fhll dtllP 

-cb-T:cL-P 

Fig{rc 18 Compdier of m1 bnin .nd livq tr}llophd 

@nenttation (4/8 wel wiSlr of tise) followins chrenic (21 

o.surivc dayt UM EtD.nt ol h.lop.ridol trd cloapi@ 

(@m@idl, svEihbl. l-lnj4liotv T-Tablcl lrd P- Pdified fom) 

(Flo a.! p

The esm@r of lirc. bypropha p).trotsc enzlne adrv y (pg&ar) in ds w6 

cffirqr oul by 'rsing slorthd n$fto{. Kytrcficrins tcvcls (tgd wurc nr0nibrud ir Urc 

Iiver ti$ues al a tine inrcfr.tr6gcd from 15 ninurcslo l2o ninut€s (Tabte 6 & 7). 

In addirion, thc cnzync lcriviry wis crtcutatcd fFm hc stopc rs x/y , 60, Mnrkcd 

indcscw6 oblcncd in lhc cnzyDc lcrivily, ptoucd dganNr 0ns al lhc tihc inlcfutol 

l5nrinuts in rcsponlc to borh hatotoidolNDd ctoz{inc rrcahcrr in a lhccxp.rincnht 

groups ofcohDcrciatty lvaitlblc and pdncd fom oihc.uncnr as cohpscd to rhcn 

r.sp€cl've conrrck (Fi8uc 19 & 20) For ihrlec. lh€ Dcr€sc m the tryprophm 

pyrole eDyme a.rivity *q signiticsl (p

.Db 6 TryPbphe prrDl& &riviry (Fdylr) in d liva foll@in8 .bui. 

.duiliib.li@ of hd.oai&|. 

0 

l5 

30 

15 

60 

?5 

90 

t05 

120 

G{id futJdll!) 

CoorDl qrl{ Bd.P c@rol H.l-l lbl.P 

1.65 

o.79 

t.71 

t.58 

1.63 

1.66 

t,72 

t,76 

t,75 

t.62 

t.06 

2.ta 

I.EE 

l.E9 

1.64 

2.6 

1.66 

t,77 

l.n 

1.97. 

t_84 

t,9l 

2.05 

1,80 

2,11 

t,67 

t:fl 

0.@ 

3.16 

3.,18 

2.to 

1.33 

l.l5 

t.00 

0,87 

0.00 000 

4.U 7.88 

4.36 3,76 

2.50 2.54 

l.E9 2.05 

f.3l ta4 

l.n r.80 

0.94 0.95 

0.88 o.EE 

. KyEMirc l"Fh(@!!} S,D,.DrO-05) w mildld h rt liE rittg.tr 0m 

' 

YEE ft Dlivity w c.lcuLld n6dF rloF aylr.60

T.!b ? Tryp|phd pymle &tivi9 (fy'sAr) i! nl liva folwitrS th. chMic 

r&niiirdid of clozrpirc (toth @i.Iy Mihblc (t bld) tnd Pui6d (lowdq 

0 

l5 

30 

a5 

60 

75 

90 

105 

lm 

Gsi8) 

(Y8/slti, 

cotrlol c|?T clr-P cdtrol Clz -T clz -P 

1.65 

0.79 

t,74 

1,58 

t.63 

1.66 

t.72 

t.76 

l,?5 

1.45 

t.t8 

1.06. 

1.20 

1.23 

t.28. 

1.10. 

t.22 

0.E4. 

r.79. 

o92. 

0.45. 

0.4E. 

l./lE 

0.54. 

0,00 

3.16 

3.48 

2.10 

1.63 

1.33 

l.l5 

l.0o 

0,87 

0.00 

4n 

2.t2 

t.60 

l.z3 

1.02 

o.13 

0.65 

0.61 

0.00 

7.16 

t.6a 

0,6 

0.,18 

l.tE 

036 

o.25 

o.22 

. Kynmie l.ck (nE I sn.,.D4.os)r@ @ildtd i!lll liE d6g rl rrim 

t YEEIG &tivi9 E .dod.r.d nw dr rlof. s t/y '60

6 

IL 

--.-cdd +HrH --FH,I+ 

F|.G 19 Rd li6 trrF.rD- DyadE dibtt UCdlr) 

fdio{i4 ftaic (21 co.sriE d.F) |/U trrtu d of 

lEloFi&l (dEEdrnly Ndhblc 0- Iri€did) e 

Frifi.d fdn) d coonol @pb. 

88

s. 

,:a 

TiD (EiD!6) 

+Cdd +CD,T -.r-Cb+ 

&G 'c Rn lit rrD.oltd t}rrd.r divily 0rg/94!) 

buovi.s cbdic (21 coariv. dry.) UM tt har of 

clodpir. (@idly .tdLlc (I-T.Ha) dd Fritr d 

tonlod codol !qL1 

E9

'|llc eNnrNic l rc ildDrl ddrDdbrcric ldlcnN w.r! usl Inr lhc Jclcnnirdi,o ol 

mlcdr w.idr ed @i qulibriv. ulysis {nh th. Qu{ y On. $n*@ 

(BioRdl} T$lc9& l0 tBn|3 rhc rfltrrnt tuolduhr wcighls ad Blaliv. quanlity of 

eh bud wirh r!.Eer to t!. tot l quliry .pplicd in 4h ld. (%) ot tlF pELin 

cdpdEr. (Pl-Pl3), In drlnion, chlmlcrillac ch.n8s w@ Bv4l.d in &nc ol drc 

por.io @mnon6lr on SDS-PAOB lollryinS chMic ft.rMl of bo$ nrbpcidol .tn 

cloapin. whici @ FG@t d in ngr 2l. Th. totci! @mtoM1 P4 hrvina mlculs 

wciot 120 KD wa do*n rc$brcd in rhc hllopcridol lolcl qFri'Dcn|ll sreups $[nc 

t. pDr.in @nFn@t Pl I hving ml.culr w.itht 43 KD w$ up E8!|lr.d folloqing 

h.lotqidol (bolh nu,ilicd and conncrcially .v.ildblc aM) l@lncnt (Fa$rc 2l & 

'l-lblc t). Moovcr, cupelul iotrotFltui.o ponc c l'2 rn'l F) luvirg nFldu|J. 

w.i8hr l8a .nd 58 KD, Gperiv.ly wo! 6h.d.d following chMic cloapin. tlanndl 

in bo|h |h. qpdinold greup6 (Fisurc 2l & T.blc l0). 

!,5 andFrlctou. Drug. .!d H.mtoloaldl Dytc.nlu 

Thc p|Bd( pm of rn|dy fo.iB d d. etiFychotic dD8 itrdBcd blood dFc@ia in 

th. ehizoglssi. p.li6& ard in D oimd bodcl (nts). Tlr. handoloSicd, biehcmic.t 

p.firears lnd hoalDlogic.l |s!65Mt w.s csi.d out .nd chonic tMlhhl of 

h.loF idol.!d cloapi@ wirh 

'!.D6r 

to mmd @fioh. Douuc conpatuon ha ben 

mdc tor 0|. *esdt of tlE &vdity of 5id. .fiect! h !r!6 by u5in8 connd.idly 

avlihblc lJn Oc nuincd fodn (Sis,na Chsnicrl lic.) ot both th* dtugs. 

ll'c hdaloloSiel indiccs including hcioSlobin comcnt'-dtion (g/dl), complcrc blood 

ccll @unr (cu.mn) r.d .t6ols!c indic (rcv (%). Mcv (n), McH (t8) .rd Mcllc 

('4)) !rc rhc nl.sc lh|| sivc inlomrrion {bo!L rlr $vdiry of lnmir ( RlplEcl lr)81). 

Mt€r' i.hi?rphEnic p.!i.rrs chDnicrllt ulrr.d with halopdidol, . sitnificdl 

(r4.C{01) dcc.!a* w.. oh..v.d in h@oglotin c.l6lntid (9J6*1.29, n=84) ad 

rh. RBC colnrs (l.9r4.r9lj n-E4) wirh . rridr &ct!& in PCV (32.61€.@, n-84), 

MCv (?9.1'954,a+ FJI). .!d MCH (t3ltr.2,r2, n-84) l@cl irdicdi.a .|Bi. 

(n8.e23} wbil. MCHC ld.l O&59j1r6, F8a) L sisriliolly G

T|!L l Coop&i.d of d! t\rt l .t@ Fd.i! Mdrioo .nq th. chllic 

.dbilirt ti6ofh.lopqid.ldd@Tii.. 

Hd.Firbl luitrcd 

'v.l'! G @ *s-D. (4, .(!ror5). 

E rr.tnt bcoc{nrdor 

QIdI' 

4.981.54 (E) 

5r6d0.55 (E) 

7.09*0.E5 (O 

6114.65 (O 

9.05*r.(rr (o 

lbnr..c 

Fco! 

0.la7l 

0.m5t 

0.0465. 

0.0m1.

KD 

n!c,r Prdd. dly$ dddpq/(t dc dntg lErd !u 

rude 2qa of lqL s hd F l& of ib l0 ta SD& 

d EFrdlg G9d Fd! lo.d F l@. t,cl FFld 

Dhorb Eiab @t. (MW-SS4ll b A A D nFlsa 

ib. codol rDpLr hoNEr/lr Lc 84 rd BF ftt !*n rh 

@cti.lly |vdLL -d Fri6.d 6.D of clouqiE .d 

v,

tDL, C@dis of Er Gu pmt i! @AoFlr ob.dd @ SDS,PAGB.ftn tbc 

chodc dni lHi@ of t{q..idot. 

P1 

P2 

t3 

14 

P5 

D6 

P7 

P8 

19 

Pl0 

Pll 

P12 

t13 

(KD) IId. P 

200 

184 

168 

t42 

t2l 

E3 

55 

5l 

45 

29 

25 

8.0 

7.4 

6.7 

8.3 

25 

EO 

72 

7.0 

7,1 

7.2 

4.2 

42 

8.9 

l0 

t2 

9.6 

2.9 

83 

84 

8.6 

r1.8 

5,9 

5,9 

7! 

8.5 

9i 

a2 

7.9 

7.2 

6,9 

6,9 

7,3

.DL l0 Cq.i.oo of tr !|m Fd.b coq@lr otsv.d d SD6-pAcB .i.' t!. 

c.hmic rbilidid of d@qn6. 

PI 

P3 

P4 

P5 

P6 

n 

PE 

P9 

Pl0 

Pll 

Pt2 

Pt3 

IlL|..d.a Wdtr. Idta|i. lra..dt % 

00) C.rtd &-r Cb-t 

r9E 

l'l.a 

120 

rvl 

8l 

63 

53 

5l 

15 

13 

t7 

62 

6.4 

6.1 

6.0 

62 

72 

2, 

7.5 

'J 

6.1 

5.7 

6.1 

5.1 

51 

6.9 

2a 

6.9 

5.1 

5.6 

5A 

5A 

6.5 

6.6 

6.3 

6.0 

6.1 

6.8 

u 

72 

6.,1 

5.9 

5.? 

5,7 

7A

cmdtratior 01.2@1.8t, RBC coDk (3.9j0.61), PCv (32.16a7,95) &d Mcv 

(80.50t8,2) dc@t slight incrc.s€ in MCH (2E,63+3Jf) &d MCfiC vah6 {36.1t6.66) 

do Dol .ltribulc io edi. (rlgun 22). W. al6o e$ some calculations for lhc initial 

$rcenine of nicru,lic oenia $ing €iydnctrc indice in ordd ro disdihinate IDA 

with $aldsmia ninor (Tdle 1l). 

ln nls, the chrcnic (21 days) r€atucnr of hatope.idot, both qp€rin€nral glups trsted 

wid co@ially rvlilalle (n=10) dd pldfi.d fom (n-lo), r6utl! in rhe signincer 

dcl)!!e (!

100 

550 

ED Rtc MCV MCI| lt|CAC 

@Co.t,ol 

- H.lop.ridol tcbzrh. 

Flglnat CoDD.dru of He[lologicrl in

Irble U C.lculdi@ u..d &r irtoDrctilg c,thro.)r. indic.s i! ordd 10 disiniftle 

two l:/pd o{ 6ic@ytic &dir: tndedi! niM |rld iror d.6cidcy- 

MCv- (5xllb) - RAC3,4 

MCV/RBC 

MCIV RAC 

Rcd blood @ll (RBC) 

MCx{r(MCD:n@ 

Iru DdLl.rcy T!.1Mboi OuRqlllt 

>13 

>3.6 

1530 

60 

€uo 

30 

20 

10 

PCV MCV MCE MCEC RDW 

Elcontrol @ Hlu @H*p rC!,T:cL,p 

Iit!ft 2l Co lxlien of tlunutotogicul irdiG tblto*i,B utrDnic 

(21 @okliE d$5) yM rlqrn ni of hdop.ridol ad cloz!,ine 

(@mcrcially wliLblc l-l.jeriod T-Tabt.r lrd P- puifi.d fom) 

Hb. h.Ndobh G/dlI IUlc-R.d blood ett .dEidid (cu.nn), tL-p-kql 

e[ sh4 o.I Mcv.Mo c btffi (q, Mct{-Md e[ hqnosbtn (rc] 

r{cxc-Ms 6rr r'dot|l$n' ..|g!rdd o{).Rrw.R.d e .|il!ihri.. ridn 

98

TrbL 12 AltdlrioD h n@ablogicol psm.rds in nrs folloving ch@ic 

adFinilrrariu of clo@ie t carmdt. 

P.rM.t B 

RBC 

PCV 

MCV 

MCH 

MCHC 

RDw 

lt.125+2.97 (8) 

5.733*0.635 (6) 

33.07s+4.8?l (8) 

54.425+1,308 (8) 

r9.05+2.85?(8) 

14.95@4.911(8) 

13.5510_735 (6) 

. vd6 e .xpra!.d i! tr@ r s.D. (n). 

ll.l66+0.781(14) 

5.686{0.32104) 

29.257+1.736 (14' 

51.51442.18804) 

t9.129tt,105 (t4) 

38.329r2.E99 0a) 

l5_0lrl+1,294 04) 

Cldrpin. Pldn d 

11.35+1.785 (8) 

5.967+0.314(8) 

28.8?5+4.681 (8) 

53.1011.398(8) 

20_875*o.62n (8) 

39j25!4266 (8' 

15_625+1.50r (8) 

' Hh- t@Clo6jn G/dl), RBC, R.d btood ccu cotu.futid (CL'm), PCv,p&*.d 6lt vol|m 

(%), Mcv-Ma c.n rcllm (fl), MCH,M@ c.ll h.flFslobin (rs), McHc- IIE& c.ll 

h.mglobin o'].ahtior (yo), RDWR.d c.lt dirtribulid wjdtn C/o).

E€lnot in tn€ $hizopt!6ic pdans (FtSurc 24), Th. 6c tHlcd viih halopdidol 

idetion sho{cd eisylsis &d hpocnrcmic cclk whil. th. nls treted sifi puincd 

aom of h.lopcridol sho*cd in addirion rc nnisoct'losis md hyDcchmmic cclh, 

micFclic celh ehd conp.rcd to thcir rcspcctivc nom@ylic-nodiehdnic conrsl 

Ets susgcstins lhaL thc lr?c oa,ncnid n1!y bc Dricocr'licrlyrchronric (FEtrre 2s) 

whil€ RBC norpholoSy rcnain non!@yic-nonnochronric h rnls lrcrlc{ wilh borh 

comm@idly aldlable md punncd fom olclozepin€ cohfomins the ab€nc€ olmmia 

Iron pofile is a useful biochcmical ft.rlcr lo cotrlinn ion defrciency whcn other 

findinss dc inco.clusivc. Si8rincd chdg6 (p

t60 

't 0o 

80 

20 

IRON 

TIBC FERRITIN %TS 

EControl t[[|!!Dttrhp.ridot @CbzlDD. 

FrgrF 24 Cmp€ris of ton ProfiL of shircpl[@ic p!ri€'r's 

cnr@i..lly t!N!.d wirh hrlop.ridol cd cloapinc. 

rM Pro6b: |'0 (ry'dr] nBc-toot iM blrlirs c+dt ta/dt] fdirii 

(r€/dD tr.s. Isru.ft.rii !&rib O{), 

l0l

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9; 

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aaE 

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Trbh 13 AlldtioG in lrm Pefil. in nt! follwirA ctmic .dhitttr.lion of 

hd@didol 6d cloeine, 

S.nm Iu flEc Fmidn Tru's.a 

rsJd rl4lD! lvdl 

163.88!42.09(9) 

!38.25117_92(8) 

82.5019.24(8) ' 

113.42+37.27(4. 

93-31+ 8.45(6). 

976.44163.44(9) 

1157.25+32.7(8r 

1590.0 88.48Gr 

r19a.7b70.21(1r. 

194E.0+30,09(6r 

. vd6 F .x!r6..d i. m t s.D. (r) . e{.05. 

r6t.25t22.6714' 

5.7211.37(8r 

5.1s10.59(8). 

73. r4i9.480r 

93.6C44(6r 

t6.79% 

|,94% 

5,188% 

6.3e4 

0vn

cloroii. eft6l lik€ v&cul.rid in cytoplM, nucle filgmatatim .rd clmD.lollsis 

wc ob$dcd i! $c roFopnil dEing difi@ntid @udng (nglrc 23), 

T.bl. 14 sulmdia tbe @mpuison of robl @d dilldErial WBC @ul in the 

$hidphrcnic palidls folNing chuic t atndt of halopdftlol od cloa!'nc. 

significei de!!e (!

11 ,rr 

Yi Y! 

9C/ 

E 

z 

7 

eE 

3E 

RE 

ZP 

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l0?

I.bl. 14 CoDpes of totd dd dilTaed.l \vBC cout i! tbc 5.htopnsic pdicnts 

followins ctmic Ecah@t oflulopdidol (n=8a) .id clozaiF (F26). 

wBc 

(o-a0) 

7525+1541 

34*12.33 

2.0*l20 

5?46*116E. 

32.88+5.75s. 

6l.03:5.931. 

2.73{O.88' 

. v.r'E @ .arE-d in @ t s-D. (n), . D4,05, lsn! laani6.d 

804{*21n. 

50.2v4D82. 

2.69+2.055.

E 

t 

E4 

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r>g 

9? 

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55 

z 9-d 

6AE 

E:3 

109

DISCUSSION

4. DISCUSSION 

4,1 ArrlFy.bo.ic Drug Tr..iD.!r, PANSS, EpS .!d potyno.Dhbm. 

Tns ml*dd $nom.llric iry h|v. impri.dion ln s.n. polymoryhi.n pan mr 

'nduccd by chrcnic ft.armcnr. Our r.sulB llppon rhe norion thar potloorphtsn is nor 

relatedblheclinic.lveiatlGincludjngaSeofpatients;aeedonselofdise6e.PANSS. 

Ou dala susgBr thal th. dos ofdtiprtlholic dru$ had sisniicdt cfecls o. psychoric 

lirtuB rnd hencc relaGd ro dcvclopffcnt of schizophrcni!. 

h rhc prcsenr ddy wc dchonslDtc 1tr0t. 0t ctitricr|y cftc.rivc dosgc, rhc sidc cntcG 

prcfile ofhalopendol aDd ctozjpi[c is sisnific,nlty diilcreni, based on rhe evaiMrion 

lionr hisrory prclilc of thc schizoplrcnic pltic s rnn oh ditTcrcnl srqcs Jurhs 

rrcalmmt Addilionally ir has b@n ob*frcd $ar drc cxrnrlrznidal srrdronrc Eps tikc 

dysrori., O,.kirre.isN,.knriisir, nd rnlivc dysknrLsir wuro sianiricrorty ruc 

@mo. in patielts tre!.d wi$ h.lopcridoli how.vcr, agmuleraosis wd signifitutly 

nor omon in tte ctoz.pin. naicd p.tior!, rspetiv€ty. The dislribution 

ch@terntic of PANSS a& us.d for thc dirgnosis or $biephtuir (r.ble 4), 6 fi€ 

&tp.tlhotic dng |rerndr cd .lsify on rhe b6is of pcitiv. or negativc dd 

oghrrrve synploms (Tugs ct .i,, 1997; Me .r d., 2ooo). 

ngurc l0 & 3l rcpBcnrs rhc coreldion rmtrsis or PANSS with dcmogr.lptricrl 

chdlcldisrics of hlbpcridot ud ctozapinc rcalql $hizophrcnic palients Gpdlivcty 

PANSS sorc rcvqls sraristic.tly signiticanl posilivc corct.rion *irh posjrive synplons 

(%l'S) d nca ivc atruloors (,z"NS) &slM vuty ir Loth hloDundot d ctoztrpiDu 

t ql.d 3chimphr.nic patiots, Th..8c at tBt onscr ot illnde shows significdr (p

nae 3a cqddd ulF,i' of P NSS ein d@s!.d&l 

dm..sli6 of H.bFidol t lcd .cnirotLaic pd.d. 

lll

Ikc lr CdrcLin !.lFir of PANSS sitt

4.2 Arllprycbotic Dme lr€dD.trr, EPS ftd DRD2 C.ft PolymorphLn 

Goelic f&tos @ftibltilg to drug indu.cd EPS have bd closly l@ked lpon by 

*uding dopdine @@tor goq, In dddition, sevcral studi6 have ained (ThohFon 

ct .1., 1997j Smd er al., 2000; Wu ct at., 2006) io idm1i6/ $e rlatioship betwm rhc 

DRD2 gae pdlmodns dd th. dEg 6!oEe o. adv@ eftetr, but ihe 6ul1s @ 

still @ltDv6ial. DI{D2 B.?ror gdc hs long b@ lle flM in lhe wh for thc 

.tiolo8]/ of $hiapnroi. (Cri(y ct .1., 2000). R€*eh fcu [s c.aId.d on D2 

E.tloF do€ to t!€ clinical elfsls of uliFy.horis ttrr w@ foud ro mai.ly bl@t D2 

re.ptoc. Cosidding th€ clirical obsd.tiotu, dopuine b?othsis, (Ktio! 1.2.3) 

wa postulated in wlich ft€ synptonr of &hibptuai. wd€ Etaled to incM€ central 

dopMindsic &tivily thar @y b€ Nociatcd with a deF6e in the nwb€i of dopmi.e 

rece9lols in sohizophraia paii€nts (Sme ct al., 2000). Mo@v6, @rtical slioh of 

long-tem dtipsrdotic dng rr.aindt n$ fto bm $ss6r€d (Lidow et rl., 1998) dd 

*ell oftlated nol*ular md noryhologio.l abnonalitiG in the 6n x (Hdison 

199.) i! &h;opbEda with th. dopqiDdec fucdon (Cdter er al., 1997; Goldsmiib 

ct al., l9?; Nddahl d a1., 2@l). 

An eiarion of the 1.4 DRD2 At .lLl. wi1h *hihpnmia sybproE EPS .rd rh€ 

ld€l ofD2 ecpior bildilg h.ve bd rcFrr.d (Ihompsr et al., 199?; Dubdtrct er st., 

2001; Nohl. cr al., 2003; Kulacli cr at., 2006). Mo@es, *vqal srudis in @njuction 

*ith ou snrdi6 bave shoM d incre& of lh. DRD2 alcl. fr.4Mcy and pB.lenc€, 

Fni@ldly in paiimt8 chrcnic.lly bqt€d wilji hdtopdidol. E()vwa, orhd lludi6 hlvc 

thoM no €vidcrc€ lor linlage or s@iadon of fie DRD2 Al all€le wnh shi@phMia 

(Nobel ei al., 2003) imludi.s EPs ad aka$kia $ G6Fd by ihe nmber ofDsMlv 

mikda (Andicd Psychiatric &siddon 1994) for th€ di!8losis ol $nizophMia. 

Thc D2 r*€plor is ore ol a1 lal five phm&ologrcauy distitut dopuire Hcptor 

fo$d otr l[. syrptic ne@B otr 1[c b6in. Th6e re€ploB de qpGscd in ncubG 

wilhin c€re!6r.ortex, ed I[. liobic srlr.m including nulos mb6, citrsula{d 

@rlq dd llc [ippedpB. Thc DRD2 6€p!o. eoe is rcgulated by rhc Taq tA 

pFnold Egio4 nncrional tudid.l. gft for shirlphrdi! di$rd6. Prcvios G@h 

show€d d Nciario. b.tsd poltnorphim jn rlre TaqlA rsion ed *hi&phMics, 

wlich is als obwed in ou lbpul.tion. I hied ro r€ €vabate tbe pEviou tiodiog in

shizophMb {Dpla &d in @ntltl mpl6 ilD P*i.trri populatim Ou fDdbg 

ruSger5 lh.r rh. i.lcriie. of th. Alal sllclc my si9i6c& ty inou@ lh. dD8 

tsloftc &d @phsizc rh. po!@tiat inportdM of Doltdor?hsh in ga* &riv.r.d 

(8eh a DRD2 86.) by @mo y p@rib.d etipsy.hotiq. ldividulr dfying rhc 

Al dlclc h.v..ppbxim*cly 30 % fcw D2 E ploB (Blh .t d., l9l) th& th@ 

witb A2 dLlc (Noblc | 99l). Si@ thc D2 @?!or gcnc @ntrols thc prcdrlion oa fi.$! 

M.proE, 0E Sndirg 6!r{s& th.t lbc Al dl.l. is re.pdlibl. for ll!. r.dudion in 

e.proi Thc mdhdir! is mt d clclr tur .dyirg 0t Al .[cl. Fduc rh. 

qp(6ion of de D2 86. c@prcd b cdryrtr8 rh. A2 .llclc. Pah.pa lu8g6lirg rh.r. 

Egulabry lia ld lbc D2 Fcpbr gq. i! .fi.c'!d j! A I crtrd 

Naallcl6c! qhilc nEy @!c!fu co.i! in rhc rMy &d nc.d ro b. nl6 itrto '@u! 

l[. i@iD8 lunbd of public.tio duing Lst y.r hrc iddti6.d tho e of 86.ric 

f.cto6 @tribuling to drw i!d&.d BPS ty cx@i.i!8 th. d@uie M?ror gaa 

I pop6. th.l th@ ir r .lrDog cmlarid emn8 DRD2 g6c DolImryhs, IDA &d 

tE EPS Cr't'nid slbh by FhiapnMic p.tid|! d.pqdot @ rhc &e .!d ldglh of 

hdopcri&l t!.d6r Cd!.qucntly, whru Dey rlrdie' bry. shoh d .lsirlio! of 

lhc DRD2 Al .llcL wirh s.bi@phMi., orh6 brw mr. Thi! .sei.lio! blr d$ bc 

drribu@d lo poouLlid sirrificalion in mG !.npl6 (Bl@quilt ct.l.,2000). lr shorld 

b. arphsiz.d rha! rh. c@?r of lid. cllct' of DtiFy.hotic drua' vai6 @Biddbly 

b.twd diflaqr !tudi6 (Blu Gr.t., t99l; Nob.t d.1,, 2000, 2003; cwo.d ct d., 

2000). Tlc @trovdry 8@6.&d i! rh. lighr or |}ir illlhd dpl.irs tbtl lte .l|orli@ in 

thc tu@tioo.l -liviti6 rnd phm@logi.d pref l. wB lugg.st d 1o b. @i.r.d *ifi 

th. polFuphi@ ad Dularid h dop@ir F.pror 8e!. or i|5 8i46. Tbc vdiot 

i?dt d hc i! . G-T tmirion .r posirio 32a27 c.rryinS SaS6llc Dur.rion i3 

iod.tcldal of thc dtug |l!.t!r6t (HlhO6idolcloapi@); m dcfliiw trr la Fr 

b@ idati6.d to th. di!.r& d drug 6por, FutlcmG th. dillcm@ in th. 

6.q@y diliibulio!, i! .edd.E. ro l!. Chi{que C2) / Hardrw.irhds 

.quilibdu, of T4 lA polFuphilm oa DRD2 96. !.ing rcR-RFLP'., stow.d 

iFB. ElqHcy of Al dl.l. h thc *hiaphFic pati6l!, .ir rc signifcan 

dififfi@ wa obldc

The Al auel€ qs found b be Mirt d with 53 (4470) of tne 120 k oM 

shizopbrtnica, dd only 12 (10"/") of the rcn-ehi2.phMi€ h€altny €onhols 

(Fig!ru 12 & l3), Altholeh no significel diflerdce {6 foud in the .ll.[c nqudcy 

in boti tne tratftnt gtuups bu1 palimh vore honozygou for a G-T ItNilion in the 

b6e pair pGitior 32827 carryinS Sq36llc nut tion. (Fi4r. 8 & 12) nowev€t, no 

iigniiml cf6ts otr rrcarndt ourcom6 w.E obwed. h .ddition, no as@ialon 

b.t@i G32827T tresirion b€tw*n cloapi.e ed halop@dol rcstoroe ws foud in 

It is likely thai the rueeltible gd6, and DNA squdcc of 3l0bp pmdNis of the 

padenls uddlline $hibpluenia depictiry nulali@ ofG-T oui side the codine rc8ron of 

the DRD2 @@!or goe is pdhaps a Esulalory !ir. for 6€ D2 @@lor soe aJfelcd in 

Al ceisE posibly influtre alrerarions ebich re phFiologcally dd clidcally 

ndinCJul l6di.g !o B?S md IDA in our populrtion. trowdd, in 8m.ral, tt?ical dd 

ltlTical dtipsFhotic dru8s, s {eU s chroric Ireal,adt, apped 1o iave diffcMt ell4ls 

on pamete6 such a EPS md IDA. 

b orcluion, my Bull! ddosirate lhat dopdinereic palhway it losd 10 be sdilive 

10 ID, whi€h @uld lcld 1o dq:6. h DRD2 @.ForE dd & in !!e in dopamirc a 

otcqv€d in aind model (Fieu. 16 r & b). 

43 Ner.otrorr tt 6 ud Artipsycbolic Dtugt 

This pan of study concludes th€ inplicatiotu of lhe thmpeltic tcspooe of dtitsychotic 

dngs, pdiculdly halopqidol md €loapi.e, in th. p.lhoph'6iology of shi&phMit, 

giva e .maSing @oelirion of rhc intoianc of albdrio$ d dilI@l 

n€@lr,l1mind p.rri.uldly dopdii. dd smlodn in vaiou. b@n egios. Thc 

dispmle sidc .fiect! pbnle oa lhac druss uoddli€s, in p!n, hay be due to tlcir 

dif@tial affnity rowdd dopuine D2 rco@to6, since lne th€rapdlio role of atFi.al 

utipsychotic dsgr i6 rclaled to the nodulatory nmtion of s@iondgic (5 m) systcD 

on dopdi!. rresnisio, (abi DdShd ct al., r99?; Melrza ci al., 2001; Abi Dd8hm 

20o7). 

!revioB studid (Abi D&ehd €r al., 197 and 2007) povidc tmlarire ryid€.c€ 

regdding fie di$rcped.s relaled to th€ rolc of th6e nemtremilIcrs and d€n

ntrrt3a Coqlioof DlIl2 gE dldic t qE* io 

td.?oidol/.L€Tar.t!-d.diDfrdofdd. 

u6

I!ft 3 cqrr(rl d ta.rylis d Drut2 !s 

ldtlrfDhio h hL?dtrol dlr "r""Tr". ft-d 

117

Gsciafion both fd ed agaiEl in ehizophFnia, HNwn, the @nbibutior of @ronin 

in Ur. psychopatlolosy of die6e cithd diftctly or vi! alcnlio$ in rhe dopdin rsb 

srstdh rlmiu elEiv€ 0qbal et al,, 1995i Lelle €t d., 2000; Rc}lotds 2OO4j 

Along lhe hid line of the bniEidn, tic di&Etc clBr€. of s@rotrqsic ncw6 e 

pllqI particuldy in nph€ nultu (BCB8) @mdtDg l)gly aI al@ of the @ntr.l 

ndoB systd by tlEir qoE, ad als @ir6 inr nDn orid elt greuls mh a 

dopditre (subsrdtia nien (Stq ad v@trd l€Smotal aF (VrAD, acetylchotin. 

(supdiu v6tibular trDleG ad @r €Pin phri!. (t@6 @qd4s (rt)) crc. Funn@r., 

the dopeindgic nbd & noslly pr€snt irr nigrcstdial (SN--CN Gaud.l€ nuct.uo & 

Puim&), ntulinbic (yTA-N,{ (Du.lcus &cmb6)) sd ih€ n€@ni.al 

(VTA+ftb61 coicx), rceioN of ihc b$al geglia, Hdopaidot, a ll,licat etip6rrhoiic 

drug atlduie rE ilive srrptom of &hircpbrenia by &rasonisn of D2 @plo. in ihe 

m.slimbic while the @a@nirdtrl blocrrd. in srriaral Egion is s$ciat€d with th. hoior 

sidc .IId& $ct s EPS. ln @nr!4 ftc djsrinctive fucrionat prefile of clo?,ljna in 

ontolling moo4 @gnirion ed mlor b.hvior i5 nodukrEd by dopmin .gic 

t'lei$ior (Mila 2000). 

An inq1!4 ir rub @dic:l !@roli. tundjon tu htlFlh6iz€d ro lE eia&d wnh 

po3rl'v. syhptoes while rhe del:Ile in DFtionr.l sbnin irncrion is lint€

Sonc d* ofthe brajn sun s mn€x, Did-brain, ttiidM, hippocmps! e $ought l0 

be inDorl@1, 4 th€y previde sP4inc sitc for ih. r.tion of etiPswholic dngs dep€nding 

on thc Dl€sce of lhe difidt ne@t'enitld @cPto6 lik 5-1IT2A and DRD2 

Mo@vF, lle eff@r of atypic.l stipayohotic, s Prdict€d bv blnli re€ptor hrlotnsis 

is cith€r by appmpriar€ nodutalion of thc D2 @@lor alode, or bv bldtadc of olhd 

E@!od Ir is mteturlhy thal thc .tpical utiD6tcholic .ftdt, Fwioclv 

EFdcd bv 

neNihlsing dal,, is n dialed by optinal D2 d@to. @uP@v whiL tbe a1!!ica!lv is 

lod in rhe pcfte of hiSh 5-HT2 dcupect Thc dtipsicholic .frd b@md Eorc 

domod.dng depdding upo! lh. fst diss@idion non lh. D2 6@tor rcSdating $. 

phtlioloSr€at EMi$ion of dopmin (Ktpu.t d.,2001_b) 

Signific&l irctw e6 obw.d in th. .oncdtarion of doPmin€ laniculdlv It 

hlpolhal@us, @nex md ltnalD in r6pon6e to dE chrDc lr€atndl ol nabp€ridol' 

bur ir nidbFin lhe cotudralion is sligh0y der@ed in boih th€ expdinental greups, 

Howwd, hatFat with clozqine rcsultd in mark d sieni6@t ds@e in all lhe 

Egios dcepr @fi.x in whjch the c.m@i.lly av.ilable fom of .lrug sbow mdkdl 

iF@e in lle @n@F.lior of dopminc (ng!rc 15 r & b) Ihis is onculmt with thc 

bylolhgis $ggeding ifibition ot d.Psi4agjc n@don via @tonqgic svsteD in {E 

mid b6in .nd for!6n! wh@ dolt of rhe dopanine temiEls e ptE4l Gult i! lhe 

El66 of

(Fteur€ 12), Thc varyinS ef€cl of rh6c dng! or ftmirM6it1€r bay e@ulfor fie 

difrFdce in i!.ir side ef*t pofile i. Espoac 10 .hm c heal,!@t. 

To elelaL bBin trrloph.r! pdiphcral br?toph$ mNt ale bc irc@cd s obrcR€d for 

livq rrrptoph& in tlp p|€gr lrlrdy Grs!rc t8). K@ll €r al., (1987) de rqoned 

inm.d eoro.i. ldek in ln. bBi! an6 cln c utipctlhotic drugs trslln.n! wbjch 

ws oorel.rcd sigifcetly vith dE b.haviodl rcspos6. Data G.ble 6 & 7) shows a 

si8lificor incrcse in tlTlophs pr@ls. &tivity 6 w€ll. Inftded lrtttopho in livd 

may a.cout for this increded dtiviry of bt?lophe plrblde involvinS subirale -t?e 

arh4cm€nt (Cih3I et al., l9?3; Bad.wy, l9?5), 

ln bEh the dtc ofs@lonin sy h6is ir stbngly inlluaEed by fte availabilily ofplM 

E}?lophan (T.8li4ont ei al., 1973) dld tldE.d l*ls of pr.ila lrt?topho md CSF 

5-t AA hav. bcd Fponed itr $hiaphdia (MarlT d al,, 2002), The l€vcl of 

rtyoph&, s it influ@B ktDffri!. (od poduct of t}?iophd calabolism 4d t-tll 

hover in both bnin @d liv{, could cll@t th€ rvailability of lhe prccusot lrrlloph&, 

in 6po@ io D.6ue lne dif€rcnlial clf@r oalratopmdol ed clozpinc, 

4.,1 E.futolo3lc.l Dysr$is .!d AntlD.yctoric Dmgs 

4.41 lrotr It tlct .cy Ardi. .nd rlTh.l Ald!6ycnodc THI'mI 

Alleration in io. m€t holim hs ba @iarcd wilh the dtipstlhotic dd8! althoush 

e sociation berwca pdipneral {d bnin iren l€v.l is difli.nll to 66t R€sllcs_legs 

sy.dhn (al€lhisi.) d EPS, relaled with halopdridol ddonstnt$ a hiSh trevaldce of 

imn dencicncy, Th€ nosl likely n€chdim oi ircn defici€n y in $€ sbizophEtric 

pad€ s is thc intdelion olneNleptio dtugs ed lhe dopdine D2 ta.plor, 6 ilafi6tr 

non d€positiotr in @dare Dels (Rnjd ct.l., 1974) pqh46 duc to lhe iM chelatjng 

prep€ny of h.lopdidol. A@rdilett iren doc e moE dyndic d|d My b€ mE 

se@tiblc ro ch.lation by n.mlcAtica at th€ oscr of irctr deficid.y (Bo Sh&he€t 

rl., l99O). Onoc ircn defioiqoy hd b€fl ind!c.!, non .toe dc dcPl€tcd ed der€fo.e 

ft noi availabl. oy nrnhd for int€r.clion witt stiptycholiG. Iurthmoe, alteraliom 

of DRD2 ra.plor nmba ws su8g.stcd !o be N6iated wiih body iron sl2tu 

p.nicddly duina imn deici@y rn6 chbnic halop@dol tEltn€nt. Con*quodx this

dec@ iren tuy augBmt lhe avaihbilily of t6 halopaidol for fie dopuine D2 

Ir rhis lh6ie I tsr.d 0F hr?orhgis thal iren d.6ciocy edi. oh6d€d in li. Pakisrari 

popllaliotr k dag-indu.ed by usin8 a @mpdative malysix oI difs€nl com.Eially 

available balopFidol dd pui6€d lEloDeridol u.d for tne bns-rern admini.tralion in 

ds nlther subsl&riare ircn deficie@y edia, My resllls suppon the idca $at the ion 

denciocy semi! itr phimph@ia parioc ould be drug,induced. 

SFiLilg dimilditi6 in the imn pDnl6 by lo.g-l€m tlalopaidol he ndt in rar od in 

ncdic!&d shizophrdis pariatl hay b. dplaincd by lhe followirg (wo hy?orh*; 

FiFlly, lonS-tcm admidst rtiotr of h.lopdidol @y modulate the ion ldcl in 

$bizophrdi.. Send, tbe ion tw.k obed.d in shizophri! n.y b. alferd by 

stipsychoij. dtug h.alnot. The hra po$ibility app.m Dorc likelt si@. a nunbd of 

stndi6 pdfofr€d in scnizophrenic patiac, on bl@d (Wsli et al., 2004 & 2006) sd 

brain ii$uc havc ben conducied in pali.nis wjth long-t€n mtipsrhotic dog hearhcnt 

iBd- Sh&h& et rl., 1990). 

This rtudy cl@ly d€lineld @ ile bsis of s€qudtial dalysis, noQhologiql &d 

bicl@i.al ê

lain region o{el$h etd., 199?; pinco cl al.,2OOO; Eriksn €t al.,2OOO) ed a numb€r 

orsludjes suppon this hypod.sis dr.t a rcduction of s.lu, ljva md braih ion tcvch in 

ral is reompanicd by r dccrc4o ir1 truhrbcr ofdoplmilc D2 rcccplor. .fhcN rru rko 

olhr faton rhar may funh.r compticdc rlE cval@tion of iron d€nciocy in patcnk. 

Chds6 in rh€ scM ion ldet io $hiaphrcnic p.(€nb Md d modcl rponcd hcrc rd 

lh{ oadelt@ iren in bmin EBaoE (Bcn_Sh&hr cr .1., 190) suppon 0E rction n 

dopamin rgic pathEy is &nritive ro ibr defciency. (Bard cr al., 1994; Cnc! d al.. 

I9r5; Net$n er al., 199?; Eriken cr d., 2oo I ). 

Thos, this srudy ron8ly suppons $c otr oftypical &ripsrnoic in developncnr of ion 

dcficiency omia iD schizophqic pati.nB. Thc io. l.vels afldred by lwo dru8s r!?.! 

dc .ot iddtical dd may (presst the advenc clf*ts oidtug rcsponse repon€d for thc 

Iist line in Pakislei shiephrnh paiicnk md the knowtedge utilized ro sppon 

pos6ible monibriog slrategis to Edwc bl@d dy$Eic fron dlipsychotic drug 

4,4.2 N€ roplil C)aororicfty, pro&h pmfit. ..d Arypiet Ardpsy.toric drug. 

l. @nlst lo &ur€ dopamiic @cplor ont soni.n $al @uB imhsti{rcly uron 

atiFychotic drug adbinjss.rion, lo.s,!am ocarlior is ,€quied for .linic.l €fiic&y ro 

rlcv.lop. Ou data nied cotu@ .bo!r hdalorosic.t 3ide effer. of ddpsychoric 

dngs, whjch do not occu acquody bur e a por€nli,l haad b sdjo$ roxicjty. 

Monnorine of doe niSht bc hclpful in .ffetivc mmagemot of drug acdon ln lhk 

roporq wc have showed crozapinc induc.

€1 al., 2oo0t cednd €t al,, 1998) m6hdism6 havd bm proposd. we d.momlrale 61% 

ilciderce ofndhophil c)lotoxicity @cu!d donng clozalre trcalrndr' 

Bio4tirati6 of cloaine to a @tiv. nctabolit (Gadld.t al, 1998) &d tne 

$b6qu@t @v.l6l bbding of llis E{.tiec intqnediale to both hulm md ra1 

ndropnil hs hd $gg6r€d s the pLsibL .xPldlrid fd . re|. in clo24iteildE€d 

rcutropnn cytoloxicity, E@ati. ctaodom. P450 azyme (Pidohe.d .l al, 195), 

MIO md pqiph.rl blood lMN (williMs .t .l-, 199, nG bd obefr€d in hul@ 

(trrrr) 10 m.bbolired cloapine into a redive inlErDediaie Po$iblv nitenim 

metalolitcs th.t cNe ct4otoxicity at il|rapcutic rlrug ondtration. P@iou snldi6 

hav€ d€mnstrarcd, all[ough n is not yet cld dr.t cloza?ire b6om€ covalddy boud 

to hum mEophilt duing theii n.brari@ or lna El.e of ltc nolrophils itrto 

pqiph€ril circutation. Tt@ is didac. io suppon tlis @nl6tion lor ddplq il is 

posible 0t't ln..oval.nt bindinS of cloapinc !o nstropbik in parids trqled with 

clozaline is not duc to @tive melabolit s gaerated by the neulrophils bd dnd to 

clozapirc rcelivc metlbolite troduc€d in lhE livd and lhd relcaed inlo the blood 

(Gadlq €t al., 1998). obwtid in rcdhl (Li! et 41, 1995) d4ost!316 lha1tu vivo 

cloz4inc D&rgo6 bepadc bioa.tivation ro s I@tire inlmcdi.re drled s 

clurarhiore @nju8.r6 (Mages .t al., | 95). 

Hoc. ! probablc ncohdjs by which n4lroPhik b4on€ .ovaLntly modifi€d bv lh. 

radiv€ helabolite is th€ r€lede of thd. d€tabolilB by 0!. livq The patiqls on 

trqhldt wilh cloapin€ in lhis study cxpcris@d odvde efcch to lhc medication. 

It@ e ccn{n p.Ellels h€twq the findings in hMd dd rals on !on8-tem cloz.pine 

tErndt rc$lding nolropni cytotoxicity. ln all €xPain@ial eimds lrst€d wit! pm 

or clJ]i)lr@ial prcp{aliG .rd paliols dp6€d to .t@4irc, dcmBftlc ndlropnil 

c,robncny (Flgor. 28 & 29) (ws! d al., 2006), Bur only 60 % of th6. prti.nti go on 

10 dw.lop crloloricitr 1lis hd lcd to suSg.stion! rhat th@ nav b. adtilioml risL 

factoc h ln. dcyclopnmt of clozqine ctLtoxi€ity. Ahough in lhk studv we did.ol 

ait@pl !o iddtify diretly the re&tive mckbotites of clozqine, but it i! ittesliry lo 

note all st g4 ofcloloxicny (Flcrr. 28). G.rdnd el al., 198!-b ha dmoGtml€d tlE 

ov.l6r birdina of r€..rive m€rrbolile of 58 KD of clozaline !o ndtrephild, 10 plav ! 

Dlc in thc ddelorbot of cloalicinduc€d cyloloxicity. b d .fon io gein turltq

isieLt inlo thc ool@ule mdheisn irvolv.d i! cloapin _induccd clotonci9, lhc 

drus nodilied prct in prelile wa comparcd. 

In additior! d iMrcluive shdy oD G&h cloz.pin. patidl showld e up regulated 

difi€dlialty qp$scd cloaline bodilicd 5E KD and 184 KD polt?cplide s opposed 

to h.lopdiilol tqr.d p@tein pbfl. lh@iry 43 KD srd 120 KD @mpondts !! drir 

doM Esulddl Gp@lively (ngrE 2l). Str|dia @ .ndflly to Puiry .!d ch@tat 

rhe rmtci!. Th.* lin6 of widetue indi..r. a Fl. for pret itr nodul.don by l@g-l€m 

cloz{line lratn.nr. The resutts premred h $h lh6ir lad support io thjs h,?olh6G 

This study al$ dphsized on lhe potential h€oalologrcal onplicadon of tie 

dtipsrcnodc dn8r, p@rib€d to lhe p.lidB of ehjaph@i. &d olttd disrd*. Tne 

belie dal: of ou popurario4 wim Uoit lioD d@ ro tto dd. !iz.; *ill h.h ir 

d€hining hdarologi.al dy$tui6; wldch k ditioal in otdd io d6ign b

CONCLUSION

5. CONCLUSTON 

L TIE mosl signilicet linding of lhc ptqql rludy is the *quace eal'sis of rhc 

3lobp mplilied trcducr ofDRD2 goe rhai sho$ rhe pr€@Ne ofc-T nllalion al bse 

pa'r posilion 32827 cdlne S€86X. in rhe Pakisbtri scniaphmic popdarion. 

Addilionallt no alsLI'on w6 foud b.nrcn allefic nlqnocy rld c T tr-rsilion 

sd cl@Aire drd h.lopdidol Epon* in *hitupbmic pari.nb .@dirg b rbc 

nomal clinical prdic. for noF rha 12 w*ks, o'ro ol ou inpondr obswarioc is 

fi.t this G-T nuialion is rot N@iarcd wiUr ttE non-shiephr€nic conttol goup, 

Mo@vd, tle segudc€ eallsis showed Do signilicor ef€cls on ircaltnol outcomes. 

2. Or rhe b6is ol PCR RFIP T &atj6is, n is.olworrhy tial lhc ftcqutuy oI Al alLt. 

dilt s sigtrificully bat*ar rh. &hiaphEnic patiots E€ard wirh haj@didol (0.44) 

ed .loatine (0.43) a @bp&€d to thei nomsl @trtmls (0.26). Th. At a.[ele w6 

fomd lo be 6s@iat.d wilh 53 (44%) of the t2O looM shizophftnics, but ws 

Beciared witn only l2 (loe/o) ofthe non+chi@ph@ic onr.l& 

3. h d€ pr@ni siudy onr rtata nis.! concm! aboul hddological side etfets ol 

dtitsrchoric drug!, which do ml @ur fr.quotly bur e a poretiat haz.d to sious 

loriciry. rlis shdy suggBts srri.g6t morilorinS rrshar $h@c dtuins rhc sfibitiry 

of haatoloeical polil. for ehi€vins tn. .linically bne!.ial .ffccb ofrhe lrahr6t. 

4, IE app.@.c of ch&acidislic cnd86 jr ihe norpbological fcalur€s oa RBC 

parl'cultrly fie pie$nce of hrlochrchic-nicN',tic c€lls (>107d, €infoEs tne 

dctdtim oat!. ofnicq'lic edia-tDA (ion deficiacy ami.). Funls validariou 

by o|!tr p@.t 8, in cpor ro rhc chmnic rrshat of hAlopqidot in $hi?opnEnic 

patiens, indicar€d rhar ft is a sid€ efel oa a drus Etna lb& a disw sr.t€ ir 

ehibphmia Addidomlly simjld resulls e@ oblaircd in @ &inal hod€l followinS 

chronic (21 rLls, WI) hqln€hl of hatopendol. Th€ €o.srsEy of th. prcmo€ of IDA 

furlia confimed by Bing i!€ €o@ercially availabl. dd pMncd powd@d fod of 

&is drug indica&d lhar |he svqity ofsidc cIlct is n@ obvios in puitied fm of 

5. Ndkophil cylotoxicnt apDEd 10 be o.o of ou imporlet findih& mosl nequen y 

obdwed in th€ pdiph@l blood s€e, in rupon* ro t]te chronic cloapir€ trearmenl in

o$ schibphmic pad€nls ed d dimal nod€l. All lh€ sbg€s of cltoloxic .fdt lile 

vdul iotr ir cylo0lND, nlclqr ltugncnrulior tu chtumnblysi$ wN obsutvtn nr t 

ncurophildurints dircrcnlill @o ins. . lr nuy bc susaBrsl $ lhc cloaPtu mcrivc 

nelllolilcs havc bclo implicaled in the loxicity bui thc m@h$isn by which lhG @cu6 

6. h .ll oxpcrindr.l eimal. aqGd wilh puiicd or conndid pr€pml'o6 md 

pad€nls expos.d io cloapine, d€nostr.tc n€utrcphil cyioloxicity sd 60 % of th6e 

pdtien$ 8o on 10 dd.lop cyotorjcny. This ha led ro su8g.stio$ fi.| lhm m 

addnionrl risk fi.r.B in Lh€ dey€lopnEd olcloapinc cyloroxicir, AhhouBh in rhis 

study I did rcr anqnpr ro id@riry diGrly tn. @tiv€ nelalolit6 of cloapin , bul il is 

inrGrins !o nolc all slag6 ofc)totoxic cfel obrd.d thrcust nisblogictl sludi6. 

7. Oor sudy dso cnrthsias DulnN u$ oil[c dirgnosric tool PANSS lbrcvulurnoD Jn'l 

chsictcnz ion ofehidphrnia, on rhc bab oaposilive and ncsrlivc sytuptonr and in 

Gponlc lo lrlic.l md at,?ical anlipsrr holic druss. 

Micrcsalclldc polymoahisnr ond conDlctc idcnrificaliotr ol tolcii *ill fudlrr 

help in lDd6landiog rh€ Ceneiq of *hizopb.ni..

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wut!@ R , !@fim JD. (19?5). ConEol of bBin nono@iE synthdis by dict dd 

plada Mim eid!- Am t Clin NuL., 28(6), 638-647. 

YdE L, LiT, wid. C, hrlclt L, Sotolofi P, Xu CI, Zag Z, S.hwanz JC, rju x, 

Mois6 HW. (193), No s@ittion h€twcd lchiz@h@ia dd homo2tl6ny .l dE D3 

dopdin recptor gde. Am J M€d coc1., 48(2), 83-86. 

Young SN. Ard@n GM, hrdy wC. (19E0). lndol@ine nelsbolkn i.6t bBin 

Etudi6 Osugh n4u€bent oftOt kDhe thrdFrlndoLeelic &id 5d in.lole&etic 

eid in cftbGpiral fluid. J. NobchcD, 34(2), 309-l 15 

lla

Y@g SN, Irttotr lvl- (200D. rb. llL of .qdonin ir Le& Dood ed ei.l 

id6.!li6 b.itht Aom dtdld tq?.00!E lcEl. Pi@L Bi@h@ Ada., ?l(4), 

85?-E65. 

zu JIL 0984). Biodrtidic.l Aldyd4 2d Ed. E sldlod C[6r Prali.oH.n 

A8A GO, McKry q Ilubbdd Jw' Mdh. KK, O99O. Applieti@ of.l*t!.p'ry 'rc 

lp.olrom.lry in ll$ i.tenrificalion of i!t8t gluoNnid! and sulphrL ooniug.l* or 

cloz4ie in r|tl. X.nobiotio4 26(5), 541550, 

zMS 1 llot C, &!g )( Y- H, Shl w' Z[d8 x em3). Irhrnr.ogadic 

{*@edi of &til6rhott.irrhEd l.dirc dy*i6ie @ltilDtid of 5blt 

qrttDtmi4 rc E prc sir. |!d of . c@lindid ord.poitu D3 wiot rlld. 

(Gry) .trd l\tosoD *ild d.re OO. a.orlu Yi x@ r'i cn|n xE zt tn.,2q7r98tuz. 

t49

APPENDICES

huPo 6th 

APPENDIX.I 

^.dd wond co.ea. ocrob" 6:1941j9!Iq 

EA.ll97 

Antipsychotic Induced Alteration in Serum 

Protein Expression of Schizophrenics 

. Using 2DE 

N. A Slrldhul, S. Zahid, A. Wssd, and R. Khan 

{.rroclErr|l..'t, Rr!. .cl| L.bo.rtory, O.grrlm.nt ot akrch.mldry, 

Unh.. dly ol K...cri, K!.rchl. Prlld.n 

2D€ 9d baJed drire.€.rliai toleome analys|s has b€€n wbely usod lo 

sn cry pali€ols' blood lo discove. p.olarin fiE kers indbalive ol dn,g olfects 

d dis€as. p.Es€g II|€ 2OE PAGE gel patt€rns. ot &hLophrcnb 

sanrn sarnd€s" d€.ndrst'at€d e rirnber ot p.otoins wuch ar6 up r€gubted 

by b.€ le.m rr.roF.idol lr6.lncnt P4, P11, P7. P!6, P1Z P23 wilh 

ute pl .ari{F tqn 82-3.5. Ar t|€ satne tim€ palieots oo cbzapino lrsat_ 

me. sioir€d si$iftcant (p

APPENDIX-Tb 

HUPO 6th Ann@lWorld ConsFq Ocr.!.r 6_lq:t07 s'oul |(oE. 

IIA- 89 

ProteomE Mapping of Healing Comeal 

Epithelial Membrane 

N. Siddiqulr, s. Musht qr, s]' z. Ali [€qvi', A Ah.aodr, 

A Wsstlt, A. A Slddlquf, end J. Shafqarr 

runk .Cty ot KlrscH, K.ractt, P.lkt.|r rAfE tft.i tj|fv..!tt 

Kerechl, Paldrt n; l(srolinsks lndtirto, l(.rel&st , Synd.i 

Oown r€gu|atbn, sFlheir o. €t€vatod a'fE rl ol firr|bcr o{ p.ol€iE ir 

Equirod f0. cdl.c€ll and cdl-olstrix ht€f&li'ls t,|at ocqr drhg $a 

normel migralion ot th€ co.nsl erilhdrun ai€r a nrdrJlcd bqrd, Wc 

hevs b€dr alt€ to coofi|m t s by lttd co.rpratw Fol€o.rE maplt|g ol 

antj{lauco.rE, ot,l€r r€lated dnlgs and g€.8 s&t{i€ h tttFli€ c.lt ot 

6bttl.o.n€a h o.!Fn cdttxs and hunan cdn€l6th6ad c.! lc. IIE 

p.ot€ans tourd to b€ diltd€nlialy srr€ss€d h tsaled cdtt€l atturril 

m€rnbran€ as cdnparcd to t4rattrg €naDl€d a d€t€rpi:t loatarEa 

ot th€s€ prot€ins in t |€ lpaJing P.oc€s.a Ort slvds u$9 dlttsn aP 

proch6s. 2-OE. Micrqtray, p€gtid€ l'$ss tlE€. p.hthg s!o\^,€d a wito 

vsri€ty ot difi6r6nc€s b€tw€€i dtgra&E atd tb.td(J''.thg co.tt€d eftilE_ 

Ital p.oi6in €r@.Bssioo both at t to t-atEcriptixtat and t-atELliqEl Lvor 

Th€lo rxoterns inctudo c€ll srtf&. glycog.oGirs' c.l adEt(n ntoS_ 

qi€s. ;tra-c.tlot6t rutlx p.oi6,.!s' valdattdr ot so'tt' ol t|e rt'diL{ 

orot hs was csrn€d o.n uslry Lnm{tpblots. kttrtro_t*no

6iiein-;fiiifd; 

APPENDl)(.II 

Cloaphe Induced Neutbphl Cltotodory iD Rrts 

ed k!d' Md tui, M.[di^. tuii, Nhed 

ab|Incr 

oj.e: rh. dldy6 onrddroudlllh h Ftbg.Hb d bnEbk Hdyloubrd qbb- 

icily6h4dnnrfuDdffiFfud@mf,lb|ydbu.ho.k'li.|nm.ndtl]d' 

k|d; n. ab F sF@a D*y €b (i{o) d6 ri MEF reiqh o. iec 

hd0d'!'Nan.b|ogg|F6trEe h (FN) d ndmelarf.e6 o' FGo! by p.iphdr M 

s' tr Fibrtud by dd rtu ey n€rhdr. tudhry sdo r0 tuen .t6 (srcl td rm 

BrdiEcqdt(rrBc)(tu u)d be srum ri{n rd (tudx 6)sE 

g@p'A|'lddl.l.ElFbwlFfu0ih9'.'h'.dFllh 

fu6:cb,c5.hddidtq|b,dyw.mfu6hboFl|fuq'q'6ffi 

d9bqutlifudfubi]ad' 

br&rodd r.ig d h !tu tu d di.r.r 

6leidr|d& bhlEdhdq (JPhs:4e). 

I rodNdo! 

cr@pho, r dib{&dir4bD i8 & 4?ii bdprycrjod.dq'wtid'PrcdfiBhmdolqia|lidooll4u' 

dytlBbtful.d..p.'n.'muhpairtdd'@be'lol.. 

dir 0.r% drdidlt |Nm4 lsulrdcr{Gis rd 'lndhc 

cy6; O' dr rrn6r) e |si&r vi6 r d cbry 

tu. nn dy qgd. Mjd F.b|m rr & ry 

ddM'€i.u'dn4ilwcFfuybdo 

d @d b oisiiod q e !5dd dFy' 

fuuld.t6dj4o'{EF{uedsdrb,la 

bg.ddymrui!kdsdi|lrol'n.cf'dfuqDDehd' 

drusoroid4.i|yh'l.d!Pohdd*8.o. 

enocdidtyliUdlr.dnidffil4d.{su' 

c|4eid'o.h6dwidl$.d.I@do'.ub 

!ra4@id@bdddEdFbGfu'Md'i4 

etra ei".d vin do'piE & @d or tuFy' 

clrc i. Fal,!d G uslr bis4 brdh, d 

tu Ei robh' orh&tud dt dd .ld 

briciiynndbyd!uor'j..'!idunAlytlE$ 

ydlnoqlqFMmyo'6e.idg!tratofcl4ii.& 

ohlddy!fu!fu'od'de36dydu.d 

fufuoI66odyw'oinvddgEedd 

dsrubdd'tb:i.i'Fodu..dn

m'4qdidu!b'fu.dDi|Iagmjd*' 

Bi.omDiolo.i.anillidofbl..d6Eawjt. 

R6drt 

M 6ddbi tus! i rlca drhdod ud 

tutubsd ndi€ Grrr ildr.uc D wote]d 

&bi4flbcloa9i*@@i|Hosw,M&&d 

mtrqbr cNh .hd.n . mdan iffi. 1D

E @hir 

carr rd ithty d..rF i rFerey..4d iidnnd 

ed Lndiddhdrc'or ciy b! rt'. i'c Ei6n by rhrcr 

dq 'Grd sqF (rierc 4 my e seqtrE ord. 6d 

IdcFd4.6i3ufd@Pircidqdrulqhis.y'G 

]nlliq'di|F!|c,16hid'!,9i!dbdBjD! 

Conclu:ion 

'q'olad[d'fuiq|{laffil!46tsei 

'}fuFibbl',Ddh*orftlEfuoisddfu3 

|rciwhd'ircfudby.qhds.prer'nily'odre|fu 

ii!6rie'id 

Refcmc6

APPENDIX-III 

HALOPERIDOL INDUCED VARIATIONS 

IN HEIVATOLOGICAL INDICES 

%n ^t, Gnet aa wtlt M) a twiqui M. 

rt h Mti:r f6 th. effdive nmlft 

or hmrblogi.al dFh!18 Herotolorior side en-a or ndrcleDtl. dtug! 

(Harop.ndoL 0.zme/Kgl,bdh6pu'rftd 

tuE.lh6.'@Rr'

tq d.ndsEy emla {IDA) ha bM deamntcd 

b b€ caus.d bt/ rh€ adddsanon of 

varlo!3 dtpsytbortc dtu8s. llowae!, io dab 

no d.nnite 6edh he erursed 10 clarlty tud 

6nnm 0E cud..l slgnln@€ of rh. t.retu. 

dd b.lv@ haropdldol .nd to.!. 

TlE ltu or tF pEn. study r. h.top.ddol 

(a butyroph..on.) hdnced h€natoloarcal 

d's(adas, 6o.laEd *tth dhrontc trcarhst 

or ddg both purllted tom dd comr.ralt 

avanable lnlecdoB on animal nod.l, host 

.onmo.ly u:.d for ti. lElftnr of $hapht6h 

ud dh€r pstrr'odc .risrded 

SUB.JECTS AND MtrTHODS 

Th. Alblno Sp€gu. D!*ley rab (n,15) wuh 

& avehse veishl of 1303 ftre dtvtded ido 

thrE 3tup: Fi6t srdp fF5) wa adnr.isbcd 

hr6m'sl.r h.lop€ddol (0.2 nglKsJ 

or plrlned tom (slsmd whne th. s.cond 

sroup (n=t va ft.Ed vitb (0.2 mglKs) 

comn rctany av.llable haloperldol tntection 

(s€.r|.) and rJE.onuols (n=5r weHubjecbd 

ro errne rtu6r. for 2l mM(u0v. days 

The r.6 w@ d@dded r3 hlM .ftd rl* 

I.lt lilEtion. wlEle blood ard w enpl6 

wea 6lld.d spaEtcly a'd ar.llzd 

Nud$e6 of preplranoN v€e mads tn du' 

plr6t€ (n-10 to. eeh A'oup). 

rb,rtr eqtr.od!F.cErtrstucrd.fisqdffi 0b.rrturiidm 

Th. hematoloAl 

al p.r.@ rTludlna hemglobln, RBC dd 

drlftmdal (ful., atEolub indt6 |rEtudtna 

h.mrooi (paci.d ell slmq PC9. M.m 

@rp!s.1nr volu@ (Mc9, d.an mrplln 

ld h.mglobh (MCH), fta @rplsld he 

noslobt. dncentErlon (McHc), red @I dn 

dbudon *idth (nDW and mo.pholoSlsl fabG 

ofRBCs via p€rtplrcral blood st:E *a 

p€rfomcd by standard lanora@ry ftthods 

S..un Ircn concntrrlon (SlC), roLl lM bhd 

lns.aprity tnBc) (Roche Lrd.) tnd ihe * 

ru6 t6ruin level (Rdndox Lid.) were deteF 

nrred. nE p€r@ntlge tdr€rh etuation 

w$.15o @lculaLdr{. Nl srds{.d .JBb6is 

v6 p.rfomd u3r4 g€ph prd pdsft :nd 

RISULTS 

kon dendenry aenla (IDA) ha b.en d{u 

medd b be au$d by th€ adnrnt$atron of 

v.rlous ddp6ychotL drw. Ho*E to date

TABLE I Conparts.n of Hemaroto3tdl 

indnee bllowLag cbontc halopeddol 

(b.rh pudned ad hjction forn) 

@tunt in B1s c F0.05) 

Pcv=F&4n{l@l$'Mcv-n,U@nxluLl 

vo|uftn'McH-nEs@l|rebh.mg|obnPs' 

nodennrte r.*r(hh6en'eB.d rod4lfy.nd 

ronfim rhe (linlcl is'rfi(da orthl intcrar 

tio. b€e@n hrloperidol ard jD.. 

fte h@.6toalcat indtc* lftlrdina h.@ 

glohin com.nlra o,.onplcr. blmd elt counr 

and absolut tndic6 (PCV, MCv, MCH and 

MCHC) aa the neasues th.r srve jntorha 

lrd abod ln. r4s&y of:ned.u. ou BUlb 

she.d rrr henoslobt .oh.enbaron ed rh€ 

RBC munr In bo(h rlF eyF imenbl mubs ro 

be siBn n( rty deftased tp < oos) E;pe. 

u\ery ArSntn@ de.ft,* (p

mercraily alallable lom i.d pudned forEl) h 

m minal mod6l Tne eqledLl anabsls b.r.d 

on th. @rpholoAbl ed bl6l'mic.l s 

md suag* dBt tE .YP or nia!.rIk-hy 

pahlmr. d.mla rr IDA- 8.oue rbn srud 

16 6d b. aniately 6s6ed on uE bets 

ofetun fefilth,.eruo rron or RBCe rotu€ 

done Th@ pal?ftteB.ppd b b. d.p€n 

deo. on 6cn o(h- rd 6 shnA as*hdon 

d be ldenund. IlE sredty otiM d.n.r.ncy 

anetu ll more obuo$ In the purtfi.d pN 

der a compdld to c'llmrclally avarhble ln 

jdim tai'Mt Ho*e*., th? trDcndkm ot 

Ih. in(@crlon of h.lop.rdol ad nm k y.r @ 

NNFtrRtrNCES 

l'ud&3€euR'Zd|GMrrrlnho.yle 

e-!dldd6dio.Fd4lEhFldo,d 

0dn!R r.&q.d.c.n,P+bby rer 32(41 

hbbgd|ffi|6hda6Eed.tqe 

ryd'd.Edre Dfugs:,.y,9:,'(d): 

3.9D8'sk!.r'&'pDn|6oIEwutrFsh.& 

4{6 j cli Byhbry 1996 a?(lr: G. 

lLus@MM'ffnd4Icdd.e6ddq,A{ 

tuh k ,elo: rs{r): r xnt. 

Fhdh6&n*ryd&'l'd,#d| 

bd'bPhaou4.uosfu|dlfuddF,dg 

d|hPu&ddnfufuldi!!F&!6N.lv!'4| 

tua Dr r w4q E |rlldosd ddr ordlFy 

tud4 JPanoFiEtfur rsc rloi e[ 

J'mwtu Mkd.rr!ffih ^mFnPir3bi 

/|r4EDidx rsrs(4:6nt 

&nrtuD&Yehm N.mb4t h(d 

{Pfd{yrde&hEt@dd].bryd 

sddi'y.l Nouck*ry trs a 10 nrrr. 

brb ss'ldd dlEBbrory:. Lyd3Mdr 

olL&r@f.fuba|'|6d6

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36 

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Nre of P.ti6l (oPnoolY S@L ID 

cdd€r: M.le/Fd.l. 

AgE at lh. 6Ft d.d of dig.: 

Dnlg u5.d fd E€.td@l: 

Dualio! of dng lre.tndtr 

A}PEI{DIX-VII 

PATIENT'S CONSENT FORM 

cbrDge i! tody wiSbt .Aq r0 w'Lt oft€rm@t 

BMI| 

chd8' in BMI: 

?Giliv. 6ymptdE: 

sddity eesd e.lo (ssA): 

Any olhd disalddid66: 

Add{ion l inJomtionl 

ConlilE.. .... ... .

Pmforme for the dirsnosis of schlzophreoi. (DSM-IV) 

in P.kistedi Schlzophreric prde ! lo evaluqte PANSS Score. 

PGiai( SvnotoN oa ScniDphr.tri. 

lamoid dcluionc, o. ddEio$ of peMnlion, 

G.osly dlrorgnlz.d or crt totric ben. or 

Afi*1 impprcpriaL to Ih€ silutior or slinlli, 

unulal motd behavio. (pcir& locking), 

D@alizarion dd somalic pr@cupalios. 

Ne.riv. 3vpproN of S.hlzopn@i. 

l&t olinld*lin lif€, low Dolivation 

Alogi! (dilficulty or inability to sleak) 

lnappbpnat€ $cial skiUs or I&kofi €r$1or lbilily to s@ializ witb oltldr peoplc 

Inability 10 mat€ fri.ntls or kep fri6d!, or not cding to h6v. fdends 

Cndiriv. Svmlo@ of S.nbdmi. 

Dimc'Jly.xprc$ing 0pughls 

Difficnlly inlegtatinS tnolghls, f.elings dd benavior

Afchen Westi

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