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Aq Nupsiquiat 2009;67(2-A):195-202

195

EFFECTIVENESS OF CLOZAPINE, HALOPERIDOL

AND CHLORPROMAZINE IN SCHIZOPHRENIA

DURING A FIVE-YEAR PERIOD

Dragan B. Ravanic1, Slavica M. Djukic Dejanovic1, Vladimir Janjic1, Suzana D. Jovic1, Dragan R. Milovanovic2,

Vladimir Jakovljevic2, Vesna Pantovic3, Boris Ravanic1, Maja Pantovic3, Mihailo M. Pantovic3

Abstract Objective: Th aim f u stu was t valuat th ffcts f lw ss f clzapin in flxibl

gim in cmpaisn with halpil an chlpmazin in lng tm. Method:Th natualistic stu was

pspctiv, activ-cntll with 325 ault utpatints f bth gns (140 fmals), with man a ag f

34.8 (ang 2157), suffing fm chnic schizphnia. Th fist nst f illnss was at th man f 27.9 as

(ang 1738), an subjcts ha th man a ag f 4.10.5 pvius lapss. Th patints w allcat

t civ halpil (105 subjcts, s ang 215 mg), chlpmazin (n=105, 100400 mg) clzapin

(n=115, 75600 mg). Th scs f pschmtic instumnts (GWB, PANSS, CGI) w gulal assss uing

5 a pi. Results: Th sixt-six spns w inclu in p-ptcl analsis: 12, 10 an 16 withpsitiv an 7, 6 an 15 with ngativ schizphnic snm in halpil, chlpmazin an clzapin

gup, spctivl. Th statisticall significant iffncs in all pschmtic scs was fun, f bth

schizphnic snms, faving clzapin. Th istibutin f ightn iffnt tps f avs vnts,

which w nt, w significantl iffnt amng tatmnt gups (2=315.7, f=34, p


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196

Schizphnia: clzapin, halpil, chlpmazin

ravanic t al.

Th cmplxit f th lng-tm cus f schiz-

phnia is cnm in numus sachs1. Whn w

cnsi phamaclgical tatmnt f schizphnia, it

is quit cla that it psnts n f th main ilm-

mas in pschiatic pactic. Th cmplxit f th pb-

lm is cnm uing a half-cntu stuggl t n

th ug with th bst fcac with minimal avs f-fcts in th tatmnt f schizphnics. Th activitis

in th l paalll th sachs in nubilg f

schizphnia paticulal nuphsilg, bichmist

an cpt phamaclg. Th iscv f nulp-

tic agnts in 1950s was vlutina an thi intuc-

tin in clinical pactic in 1960s allw x juvantibus ap-

pach t th unstaning f th natu an functin

f pamingic pathwas, which w th minant ta-

gt f ths ugs.

Th sachs als shw that nulptics an th-

antipschtic agnts chang schizphnia. Th a

spcic f n fw smptms but nt f th isas

p s1,2. Until 1980s th main thaputic appach was

iminishing clinical malitis, smptms in pschpa-

thlg lik hallucinatins, lusins an thught istu-

bancs. With th wks f Cw an assciats in th a-

l 1980s an th cncpts f iviing schizphnia int

tp I an tp II2 th nw ilmmas mg. Th main

pblm was th qustin f chnic schizphnia, pa-

ticulal ngativ smptms3. This gap btwn ug f-

cac an th clinical n pn th pssibilit f fu-

th basic an clinical sachs t n m vali an

pictiv citia f antipschtic us within bth tp-ical an atpical classs4.

Tpical, incisiv antipschtic ugs w nt capabl

t fulll mans in th cu f ngativ schizphnia,

th i it patiall an with a lt f avs ffcts. Th

intuctin f nvl, plvalnt, atpical antipschtics

pn an xciting sach aa, which minat in bth

clinical an sach pactics uing th lat 1980s, an

al 1990s. Bth classs blck a lt f amin cpts, but

main iffncs mg in pamingic d2 pathwas.

Th classical nulptics a stng d2 antagnists but

th ispla cnsiabl afnit t th main nutans-

mitt sstms in bain. on th th han, th atpical

ns shw lss afnit f pamin cpts, paticula-

l f d2, but ptntl amliat th cpt tps5,6.

Aft cas f basic an clinical sachs, clzap-

in has bn stablish as a stana f th mst sv

tp f this is, th tatmnt-sistant schizph-

nia, as wll as f chnic, fquntl lapsing patints.

Hwv, th a still man bats abut supmac f

th atpical ugs v ali micatin. In aitin,

mix fms f isas in which psitiv an ngativ

snms xist in paalll a still inaquatl tat-

. It sms that htgnit f this subppulatin f

schizphnics was th basis f th pblm. Unftunat-

l, ths patints minat in clinical pactic an, bvi-

usl, th must b iniviuall tat. Th tatmnt al-

githms, which a v usful f wll-stablish an

iffntiat fms f schizphnia, hav littl pacti-

cal bnt. Futh, simila lng-tm stuis with clzap-

in a scac an iffnt fm us; f xampl thw f tspctiv natu7, having iffnt stu pp-

ulatin (.g. fmals)8, incluing wi uatins f fllw-

ups9 aiming at islat utcms10.

Taking all this int accunt, u pima aims w t

invstigat th fcac f th nulptics with iff-

nt stuctu an phamaclgical an clinical pl in

th cus f schizphnic is in lng tm tat-

mnt, incluing th saft f th stu micatin in

bth psitiv an ngativ tps f schizphnia. Th

aim f u stu als was t iffntiat th ffcts f

lw ss f clzapin in xibl gim in cmpaisn

with tw tpical nulptics, halpil an chlp-

mazin in lng tm.

METHOD

Th clinical stu was pspctiv, activ-cntll with

utpatints suffing fm schizphnia an th fllw up f 5

as. Inclusin citia w: aults v 18 as f ag, bth f

gns, iagnsis f schizphnia stablish b dSM-IV cit-

ia, th psnc f psitiv an ngativ smptms, pviusl

tat with antipschtics which w infcint an with th

hist f si ffcts. Pvius antipschtic ugs w iff-

nt fm th stu antipschtics. exclusin citia w: un18 as f ag, tatmnt naiv schizphnics, pgnant wm-

n, signicant mntal an/ smatic c-mbiit, schizph-

nia lasting f 10 as m an fusal f th patints thm-

slvs h his lgal psntativ t paticipat in th

stu. Th stu was cnuct uing th pi btwn 1998

an2003 at th Pschiat Clinic f th Clinical Cnt Kaguj-

vac. Th allcatin f th patints in th stu ams fllw

pagmatic (natualistic) sign11. It mans that tatmnt allca-

tin f stu subjcts was nl gvn b clinical pactic ci-

tia in u cunt, nt b subjct stu status. Thf, th

patints w tat within th stting f gula clinical pac-

tic, at th cst f stu which was incpat int gula

Natinal Halth Svic funing schm, an th was n n

f an spnsship (.g. ugs, sach stuff, pschiatists).

Th numb f pvius schizphnia lapss, galss t

which antipschtic ugs w pviusl pscib, was th

main citin f paticula antipschtic chic. Halpil

was assign t patints having


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ravanic t al.

as ths patints w cnsi t b tatmnt-sistant. Th

psnc f mil-t-mat cncmitant isas which cul

b wsn b stu micatin (.g. mtablic snm, v-

inc f ahthmias ischmic hat isas, caimpa-

th) was cnsi nt t b an cntainicatin p s f

stu ugs an th patints with ths iss w initial-

l tat with lw-ss f antipschtic ugs with clsclinical fllw-up v six mnths. Th w allw t hav

cncmitant micatins pscib b apppiat spcialist

xcpt f th intactins with halpil, chlpmazin

clzapin. Th ugs w us in appv inicatins an s

gimns. Paticipatin in th stu was cmpltl vlunta,

infm cnsnt was btain, an thical pincipls w in

accanc with Hlsinki dclaatin. Th stu sign was cn-

si an accpt b thical ba f th Pschiat Clinic.

Th th ugs w us as activ tatmnt in mn-th-

ap. Th st gup f patints civ halpil, in s

ang 215 mg, ail, all. Th scn gup civ chl-

pmazin, in s ang f 100400 mg, ail, all. Th nal

gup civ clzapin, in s ang 75600 mg, ail, al-

l. ds angs w chsn accing t th usual pactic in

u cunt12 an in accanc with sm th auths8. dss

f all th ugs w ajust accing t clinical spns.

dail ss w aminist in n m (gnall in 23)

ptins. oth micatins w us accing t th clinical

n, but this xclu th antipschtic ugs.

Th clinical fficac was stablish using th fllwing

pschmtic instumnts: Psitiv an Ngativ Snm

Scal-PANSS13, Clinical Glbal Impssin Scal-CGI14 an Gn-

al Wll-Bing Scal-GWB15. Th scal scs w calculat

at baslin, aft 6 wks, 3 mnths, 12 mnths an annuall.

Aftmath, a numb f patint visits was ajust accing

t clinical n. In gnal, th visits at tatmnt intuctin

w wkl an aft satisfact clinical spns, mnthl.

Th saft f tatmnt was valuat b CGI (subscal f -

cing an assssing v avs clinical vnt). Th patintsw withawn fm th stu in th cas f: n satisfact

clinical spns, sius avs ffcts a patint withw

n his h wn will.

Assssmnt f th gnal status (GWB) was stimat in

th scal an sc b th pschiatist fm 0 (th wst) t

110 (th bst). Th PANSS scal scs w us t assss ps-

itiv smptms (PANSS-P), sc fm 7 (th bst) t 49 (th

wst), ngativ smptms (PANSS-N) sc fm 7 t 49 an

gnal pschpathlg (PANSS-G) sc fm 16 t 112. Th

CGI scal was us t sc: a) svit f illnss (SI) which -

n th svit f illnss, fm 1 (nmal) t 7 (mst xtml

ill), b) glbal impvmnt (GI), fm 1 (v much impv) t

7 (v much ws) c) thaputic ffct (Te) fm 1 (unchang

ws) t 4 (vast impvmnt), an ) avs ffcts (Ae),

fm 1 (nn) t 4 (utwigh thaputic ffct). efcac inx

(eI) was calculat b iviing th man Te sc with th man

Ae sc (eI=Te/Ae).

Th stu ata was analz b th mths f scip-

tiv statistics, t-tst (f cntinuus numic vaiabls) an chi-

squa tst (f fquncis)16. Hpthsis tsting was n in

tw-si pcu wh th lvl f statistic signicanc was

stablish at p0.05.

Table 1. Demographic and clinical properties of the study population.

Vaiabl Halpil gup Chlpmazin gup Clzapin gup

Numb f subjcts 105 (100%) 105 (100%) 115 (100%)

Man ag at isas nst (ang) 29.09 (1741) 28.09 (1938) 24.52 (1932)

Man ag at stu nst (ang) 34.71 (2357) 38.52 (2156) 33.60 (2455)

Gn (m/f) 70/35

(66%/34%)

60/45

(57%/43%)

55/60

(48%/52%)

dminant ngativ smptms 35 (34%) 40 (38%) 50 (44%)

dminant psitiv smptms 70 (66%) 65 (62%) 65 (56%)

Pvius lapss 3.70.5 3.90.6 5.30.5

Man ail ss, mg (ang)

duing 1st a

duing 5th a

duing all stu

9.2 (615)

4.9 (212)

6.8 (215)

358.4 (100400)

212.8 (100350)

294.5 (100400)

443.6 (150600)

158.4 (75450)

198.4 (75600)

Withawals at 1 a (n) 31 35 27

Withawals in 25 as (n) 55 54 57

Inclu in p-ptcl analsis (n) 19 (18.1%)

7 ngativ

12 psitiv

16 (15.28%)

6 ngativ

10 psitiv

31 (26.9%)

15 ngativ

16 psitiv


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ravanic t al.

RESULTS

Th main mgaphic an clinical pptis f th

patints a psnt in Tabl 1. In gnal, n signicant

htgnit amng tatmnt gups was fun an

th gups w cmpaabl accing t th main clini-

cal an mgaphic pptis, at baslin.

Th scs f pschmtic vaiabls a psnt

in tails in Tabls 2, 3 an 4. Th man iffnc b-

twn PANSS psitiv an ngativ sub scs was 29.1%.

F th pups f calculatin, th valus f th ttal

scs w us, at baslin, aft a a an 5 as f

tatmnt, accing t th lng-tm utcm tacing. In

gnal, th sults shw th iffnc btwn stu

micatins fcac an th gatst an statisticall sig-

nicant clzapin fcac. Hwv, halpil an chl-

pmazin w als fcacius, but with spns vai-

abilit in patints with psitiv an ngativ smptms.

In th patints with psitiv schizphnic snm,

th cmpaisn f clzapin with halpil an chl-

pmazin shw gat fcac f th fm an

statistical signicanc in th iffnc f all pschmt-

ic scs. Hwv, in th PANSS-N sub scs an CGI-

SI sub scs clzapin shw highl signicant iff-

nc in ffctivnss. In th patints with ngativ schiz-

Table 2. The psychometric scores in the haloperidol group.

yas GWB PANSS-P PANSS-N PANSS-G SI GI eI

Halpil gup with minant SCH+

0 32.8

7.04

30.38

6.92

20.08

5.62

51.46

15.81

5.15

1.08

1 48.12

10.59

23.86

5.91

16.62

3.99

45.77

9.46

4.77

1.38

3.25

0.88

0.79

0.22

5 53.46

15.39

22.13

6.13

15.94

3.65

42.08

9.18

4.2

1.06

3.07

0.8

0.89

0.26

Halpil gup with minant SCH

0 40.37

8.48

20.5

6.15

24.5

6.13

41.25

12.55

4.56

1.15

1 47.75

13.33

18.5

4.47

22.45

5.4

39.54

11.27

4.18

0.98

3.25

0.66

0.71

0.18

5 55.82

16.52

17.42

4.44

19.5

4.63

37.21

8.06

3.87

0.8

3

0.73

0.76

0.17

Th valus psnt th man (stana viatin); GWB: assssmnt f gnal status; PANSS-P: psitiv smptms; PANSS-N: ngativ smptms;

PANSS-G: gnal pschpathlg; SI: svit f illnss; GI: glbal impvmnt; eI: efcac inx; SCH(): minant psitiv/ngativ smptms.

Table 3. The psychometric scores in the chlorpromazine group.


Chlpmazin gup with minant SCH+

0 39

11.7

28.79

6.7

20.57

6.04

48.36

13.06

4.9

1.25

1 49.64

14.4

23.86

6.12

18.86

5.75

38.93

8.21

4.22

1.27

3.36

0.84

0.69

0.19

5 59.43

16.05

21.14

5.71

17.1

5.09

37.93

9.97

4.15

0.98

3.26

0.84

0.71

0.17Chlpmazin gup with minant SCH

0 37.29

10.52

19.29

5.4

23.14

6.71

43

11.67

4.61

1.16

1 49.29

14.5

17.71

4.51

20.57

5.97

39.45

10.08

4.02

0.93

3.21

0.93

0.73

0.17

5 51.73

15.05

16.72

4.07

17.85

4.71

38.1

8.44

3.82

0.87

2.95

0.7

0.81

0.18




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ravanic t al.

Table 4. The psychometric scores in the clozapine group.


Clzapin gup with minant SCH+

0 32.62

7.83

32.15

6.93

24.24

5.75

52.77

13.72

5.74

1.22

1 57.31

15.47

23.31

5.54

18.38

4.96

40.62

10.91

4.32

1.21

2.86

0.75

2.15

0.58

5 59.15

12.42

21.97

5.27

15.88

3.49

36.12

9.53

3.91

1.01

2.25

0.55

3.2

0.71

Clzapin gup with minant SCH

0 40.2

11.26

22.4

6.27

24.4

6.59

44.6

11.08

4.8

1.2

1 57.4

12.34

18.8

5.45

18

4.76

33.75

9.13

3.62

0.97

2.4

0.62

2.09

0.49

5 69.2

16.58

16.48

4.86

15.12

4.4

30.8

8.72

3.2

0.95

2.2

0.54

3.1

0.75



Table 5. Safety proles of study drugs.

Avs ffcts

Halpil Chlpmazin Clzapin

N % N % N %

dstnia 67 30.3 22 6.7 1 1.0

Akathisia 55 24.9 47 14.2 1 1.0

Baikinsia 16 7.2 68 20.6 14 14.6

rig 52 23.5 19 5.8 0 0.0

Tm 27 12.2 24 7.3 2 2.1

dskinsia 32 14.5 12 3.6 0 0.0

Satin 2 0.9 28 8.5 20 20.8

Cnvulsin 3 1.4 3 0.9 1 1.0

Antichlingic ffcts 2 0.9 27 8.2 12 12.5

Hpsalivatin 2 0.9 6 1.8 11 11.5

Hptnsin 5 2.3 42 12.7 13 13.5

Ahthmia 1 0.5 5 1.5 3 3.1

Bl scasia 2 0.9 5 1.5 9 9.4

Hpplactinmia 12 5.4 9 2.7 1 1.0

Wight changs 3 1.4 8 2.4 4 4.2

dslipimia 4 1.8 4 1.2 2 2.1

Glucs intlanc 1 0.5 1 0.3 2 2.1

Skin actins 2 0.9 4 1.2 1 1.0

Ttal 221 100 330 100 96 100

Numb f avs

vnts p patint

2.7 3.2 0.9

N: numb f patints xpincing th actin; istibutin signicantl iff (2=315.7, f=34, p


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ravanic t al.

phnic snm, th cmpaisn f clzapin with

halpil an chlpmazin shw much gat-

fcac f th fm an gat statistical signi-

canc in th iffnc f all pschmtic scs. Th-

f, th t-tst valus f iffncs f man abslut

changs f pschmtic scs btwn halpil

(n=12) gup an clzapin gup (n=16) in psitiv schiz-phnic snm at th nal visit (aft 5 as f tat-

mnt) f GWB, PANSS-P, PANSS-N, PANSS-G, PANSS-T,

an SI w 2.21 (f=26, p


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ravanic t al.

tints with schizphnia tat with clzapin n a lng-

tm basis, th signs f mtxicit w fun24. In an-

th stu, tachcaia, hptnsin an satin isap-

pa uing th initial phas f tatmnt (i.. 46 wks),

as tlanc vlp with cntinuatin f thap12. In

u stu w w nt paticulal cncn with spcic

masus f th patints qualit f lif. Hwv, u ap-pach fllw th clinical ffcts f clzapin in multi-

imnsinal pattn, as ths suggst25. ovall, all ma-

sus cnm th ffctivnss an saft f clzapin.

Th slctin bias, high p ut at an man ss

a ptntial stu limitatins. Th patints in clzapin

gup ha sm m lapss at baslin an smwhat

high pschmtic scs, but this was nt statisticall

signicant. Nvthlss, this fact might suggst th ps-

nc f a slctin bias which cul ptntiall istt

nal sults. Hwv, th bias i nt iminish th cl-

zapin fcac at th n f stu, likl u t its m

plvalnt, uniqu cpt phamaclg than th an-

tipschtic ugs26. Th slctiv changs in nutans-

missin puc b clzapin antipschtic actin w

ath tim-pnnt than s-pnnt, which ma

b a asn f la thaputic activit27 an als th

ffctivnss f mat t lw ss in u stu.

In u stu, th high p ut at nt, but this

fact clats wll with th stuis in bth st-pi-

s schizphnia28 an paticulal chnic schizphn-

ic patints29. Th mst fqunt asns f iscntinua-

tin w a ugs insufcint ffctivnss, avs f-

fcts, th patints nncmplianc. Thf, as it iswll-knwn that p ut at, in gnal, was ath high

an incas uing th stu, w analz spnsiv

subjcts nl (p-ptcl analsis) bcaus w w in-

tst nl in ug ffctivnss n subtitl pschmt-

ic malitis but nt in ugs ffcts n th whl stu

ppulatin. In anmiz cntll tials, high ss f

th scn gnatin f atpical antipschtics incluing

clzapin w us t puc all almst all th clini-

cal spnss f th ug30. Althugh in a cass w us

v high ss, in th majit f patints clzapin man

ss w small. Hwv, u stu was pfm in

natualist sttings in which xibl, ath x ss a

m apppiat12. oth stuis cnm th ffctiv-

nss f clzapin in xibl s schuls uing th lng

tm thap31,32, an als incluing v small ss8.

In cnclusin, th lng tm, v-a us f lw s

f atpical antipschtic, clzapin, in xibl gim,

givs satisfing clinical ffctivnss an shws its sup-

iit t halpil an chlpmazin. Th saft p-

l f clzapin was btt than th stu ugs. ou

stu cnm th n f signing an cnucting

th lng-tm, clinical stuis in natualistic, utin clini-

cal pactic sttings with multiimnsinal appach.

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