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The New England Journal of Medicine

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#oyrigh" $ 200% Ma!!achu!e""! Medical &ocie"y. 'll righ"! re!er(ed.
The ne w engl
and
journal of medicine
e!"a)li!hed in 1*12 !e"em)er 22, 200% (ol. +%+ no. 12
Effec"i(ene!! of 'n"i!ycho"ic Drug! in ,a"ien"!
wi"h #hronic &chi-ohrenia
Jeffrey '. .ie)erman, M.D., T. &co"" &"rou, M.D., M.,./., Jo!eh ,. McE(oy, M.D., Mar(in &. &war"-, M.D.,
0o)er" '. 0o!enhec1, M.D., Diana 2. ,er1in!, M.D., M.,./., 0ichard &.E. 3eefe, ,h.D.,
&onia M. Da(i!, Dr.,./., #larence E. Da(i!, ,h.D., 4arry D. .e)owi"-, ,h.D., Joanne &e(ere, M.&.,
and John 3. /!iao, M.D., for "he #linical 'n"i!ycho"ic Trial! of 5n"er(en"ion Effec"i(ene!! 6#'T5E7 5n(e!"iga"or!8
a)!"rac"
background
The rela"i(e effec"i(ene!! of !econd9genera"ion 6a"yical7 an"i!ycho"ic drug! a!
com9 ared wi"h "ha" of older agen"! ha! )een incomle"ely addre!!ed, "hough newer
agen"! are curren"ly u!ed far more commonly. :e comared a fir!"9genera"ion
an"i!ycho"ic, erhena-ine, wi"h !e(eral newer drug! in a dou)le9)lind !"udy.
methods
' "o"al of 14;+ a"ien"! wi"h !chi-ohrenia were recrui"ed a" %< =.&. !i"e! and
random9 ly a!!igned "o recei(e olan-aine 6<.% "o +0 mg er day7, erhena-ine 6* "o
+2 mg er day7, >ue"iaine 6200 "o *00 mg er day7, or ri!eridone 61.% "o ?.0 mg
er day7 for u "o 1* mon"h!. @ira!idone 640 "o 1?0 mg er day7 wa! included af"er
i"! aro(al )y "he Food and Drug 'dmini!"ra"ion. The rimary aim wa! "o
delinea"e difference! in "he o(erall effec"i(ene!! of "he!e fi(e "rea"men"!.
results
2(erall, <4 ercen" of a"ien"! di!con"inued "he !"udy medica"ion )efore 1* mon"h!
610?1 of "he 14+2 a"ien"! who recei(ed a" lea!" one do!e7A ?4 ercen" of "ho!e
a!!igned "o olan-aine, <% ercen" of "ho!e a!!igned "o erhena-ine, *2 ercen" of
"ho!e a!9 !igned "o >ue"iaine, <4 ercen" of "ho!e a!!igned "o ri!eridone, and <;
ercen" of "ho!e a!!igned "o -ira!idone. The "ime "o "he di!con"inua"ion of
"rea"men" for any cau!e wa! !ignifican"ly longer in "he olan-aine grou "han in "he
>ue"iaine 6,B0.0017 or ri!eridone 6,C0.0027 grou, )u" no" in "he erhena-ine
6,C0.0217 or -ira!idone 6, C 0.02*7 grou. The "ime! "o di!con"inua"ion )ecau!e of
in"olera)le !ide effec"! were !imilar among "he grou!, )u" "he ra"e! differed 6, C
0.047D olan-aine wa! a!!ocia"ed wi"h more di!con"inua"ion for weigh" gain or
me"a)olic effec"!, and erhena-ine wa! a!!ocia"ed wi"h more di!con"inua"ion for
eE"rayramidal effec"!.
conclusions
The majori"y of a"ien"! in each grou di!con"inued "heir a!!igned "rea"men" owing
"o inefficacy or in"olera)le !ide effec"! or for o"her rea!on!. 2lan-aine wa! "he mo!"
ef9 fec"i(e in "erm! of "he ra"e! of di!con"inua"ion, and "he efficacy of "he con(en"ional
an"i9 !ycho"ic agen" erhena-ine aeared !imilar "o "ha" of >ue"iaine,
ri!eridone, and -ira!idone. 2lan-aine wa! a!!ocia"ed wi"h grea"er weigh" gain and
increa!e! in mea9 !ure! of
gluco!e and liid me"a)oli!m.
The New England Journal of Medicine
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#oyrigh" $ 200% Ma!!achu!e""! Medical &ocie"y. 'll righ"! re!er(ed.
From "he Dear"men" of ,!ychia"ry, #ollege of ,hy!ician! and &urgeon!, #olum)ia =ni9 (er!i"y, New For1 &"a"e
,!ychia"ric 5n!"i"u"e, New For1 6J.'...7D "he Dear"men" of ,!y9 chia"ry, &chool of Medicine 6T.&.&., D.2.,.7,
and "he Dear"men" of 4io!"a"i!"ic!, &chool of ,u)lic /eal"h 6&.M.D., #.E.D.7, =ni(er!i9 "y of Nor"h #arolina a"
#hael /ill, #hael /illD Guin"ile!, 0e!earch Triangle ,ar1, N.#. 6&.M.D.7D "he Dear"men" of 4iological ,!y9
chia"ry, John =m!"ead /o!i"al, 4u"ner, N.#. 6J.,.M.7D "he Dear"men" of ,!ychia9 "ry and 4eha(ioral
&cience!, Du1e =ni(er9 !i"y Medical #en"er, Durham, N.#. 6J.,.M., M.&.&., 0.&.E.3.7D "he Dear"men" of ,!y9
chia"ry, Fale =ni(er!i"y &chool of Medicine, New /a(en, #onn. 60.'.0.7D and "he Di(i9 !ion of &er(ice! and
5n"er(en"ion 0e!earch, Na"ional 5n!"i"u"e of Men"al /eal"h, Na9 "ional 5n!"i"u"e! of /eal"h, 4e"he!da, Md.
64.D..., J.&., J.3./.7. 'ddre!! rerin" re>ue!"! "o Dr. .ie)erman a" "he Dear"men" of ,!ychia"ry, #ollege of
,hy!ician! and &ur9 geon!, #olum)ia
=ni(er!i"y, New For1 &"a"e ,!ychia"ric
5n!"i"u"e, 10%1 0i(er!ide Dr., New For1,
NF 100+2, or a" jlie)ermanH
colum)ia.edu.
8The #'T5E in(e!"iga"or! are li!"ed in "he
'endiE.
N Engl J Med 200%D+%+A120;92+.
Copyright 2005 Massachusetts Medical Society.
n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
120;
The new england journal of medicine
n"i!ycho"ic drug! ha(e
)ecome "he corner!"one of "rea"men"
for !chi-o9 hrenia. The fir!"9
genera"ion Icon(en9
"ionalJ an"i!ycho"ic drug! are high9affini"y an9
"agoni!"! of doamine D2 rece"or! "ha" are mo!"
effec"i(e again!" !ycho"ic !ym"om! )u" ha(e
high ra"e! of neurologic !ide effec"!, !uch a!
eE"rayrami9 dal !ign! and "ardi(e dy!1ine!ia.
1
The in"roduc"ion of !econd9genera"ion, or
Ia"yical,J an"i!ycho"ic drug! romi!ed
enhanced efficacy and !afe"y.
2
The a"yical agen"!
differ harmacologically from re(i9 ou!
an"i!ycho"ic agen"! in "heir lower affini"y for
doamine D2 rece"or! and grea"er affini"ie! for
o"her neurorece"or!, including "ho!e for !ero"onin
6%9hydroEy"ry"amine
1'
,
2'
,
2#
,
+
,
?
, and
<
7 and
nor9
einehrine 6a
1
and a
2
7.
1
'l"hough !"udie! indica"ed "ha" "he a"yical
drug! are !imilar "o "he con(en"ional drug! in
reduc9 ing !ycho"ic !ym"om! and roduce few
neuro9 logic effec"!, "he e(idence of "heir !uerior
efficacy ha! )een nei"her con!i!"en" nor ro)u!",
+9*
wi"h "he eEce"ion of clo-aine, which reea"edly
ha! )een effec"i(e in a"ien"! who!e condi"ion i!
refrac"ory "o "rea"men" wi"h o"her "ye! of agen"!
)u" ha! !e(ere !ide effec"! "ha" limi" i"! u!e.
;911
The newer agen"! aear more efficaciou! "han
con(en"ional drug! in reducing nega"i(e
!ym"om! 6e.g., lac1 of emo9 "ion, in"ere!", and
eEre!!ion7, o!!i)ly owing "o "he a)!ence of
eE"rayramidal !ym"om!
12
or o"her !ec9 ondary
cau!e! of nega"i(e !ym"om! 6e.g., dere!9 !ion7
ra"her "han "o direc" "heraeu"ic effec"!.
1+
The re!ul"! of !"udie! of "he effec"! of "rea"men"
on cogni"i(e imairmen" and mood !ym"om!
ha(e )een inconclu!i(e.
14,1%
The a)ili"y of a"yical
agen"! "o re(en" rela!e and "heir effec"! on
!ocial and (oca"ional func"ioning, >uali"y of life,
long9"erm ou"come, and "he caregi(er!K )urden
ha(e )een in9 comle"ely eElored.
*,12,1?
The !afe"y ad(an"age! of "he a"yical drug!
ha(e )een >ue!"ioned )ecau!e of "heir roen!i"y
"o in9 duce weigh" gain
1<
and al"er gluco!e and
liid me9 "a)oli!m.
1*,1;
Ne(er"hele!!, "he!e
medica"ion! are widely u!ed and ha(e a ;0
ercen" mar1e" !hare in "he =ni"ed &"a"e!,
20,21
re!ul"ing in )urgeoning co!"!. 5n "he wa1e of
"hi! "rend, >ue!"ion! ha(e )een rai!ed a)ou" "he
clinical ad(an"age! and co!" effec"i(ene!! of "he
a"yical drug!. :e reor" "he rimary ou"come!
of a dou)le9)lind, ac"i(e9con"rol clinical "rial
!on!ored )y "he Na"ional 5n!"i"u"e of Men"al
/eal"h 6N5M/7 "ha" wa! de!igned "o com9 are
"he effec"i(ene!! of a"yical and con(en"ional
an"i!ycho"ic drug!.
22,2+
a
me"hod!
study setting and design
The #linical 'n"i!ycho"ic Trial! of 5n"er(en"ion Effec"i(ene!!
6#'T5E7 !"udy wa! ini"ia"ed )y "he N5M/ "o comare "he
effec"i(ene!! of an"i!ycho"ic drug!. 5"! ra"ionale, de!ign, and
me"hod! ha(e )een de!cri)ed re(iou!ly.
2492*
The ro"ocol wa!
made a(aila)le "o "he u)lic for commen", and a commi"9 "ee of
!cien"ific eEer"!, heal"h care admini!"ra"or!, and con!umer
ad(oca"e! cri"i>ued "he !"udy under "he au!ice! of "he N5M/. The
!"udy wa! conduc"9 ed )e"ween January 2001 and Decem)er 2004
a" %< clinical !i"e! in "he =ni"ed &"a"e! 61? uni(er!i"y clin9 ic!, 10
!"a"e men"al heal"h agencie!, < Le"eran! 'f9 fair! medical cen"er!, ?
ri(a"e nonrofi" agencie!,
4 ri(a"e9rac"ice !i"e!, and 14 miEed9!y!"em !i"e!7. ,a"ien"! were
ini"ially randomly a!!igned "o recei(e olan-aine, erhena-ine,
>ue"iaine, or ri!eri9 done under dou)le9)lind condi"ion! and
followed for u "o 1* mon"h! or un"il "rea"men" wa! di!con9 "inued
for any rea!on 6ha!e 17. 6@ira!idone wa! aro(ed for u!e )y
"he Food and Drug 'dmini!9 "ra"ion MFD'N af"er "he !"udy )egan
and wa! added "o "he !"udy in January 2002 in "he form of an iden9
"ical9aearing ca!ule con"aining 40 mg.7 ,a"ien"! who!e a!!igned
"rea"men" wa! di!con"inued could recei(e o"her "rea"men"! in
ha!e! 2 and +.
24
The re!en" reor" i! limi"ed "o ha!e 1 re!ul"!.
participants
Eligi)le a"ien"! were 1* "o ?% year! of ageD had
re9 cei(ed a diagno!i! of !chi-ohrenia, a!
de"ermined on "he )a!i! of "he &"ruc"ured #linical
5n"er(iew of "he Diagnostic and Statistical Manual of
Mental Disorders, four"h edi"ionD and were a)le "o
"a1e oral an"i!y9 cho"ic medica"ion, a!
de"ermined )y "he !"udy doc9 "or. ,a"ien"! were
eEcluded if "hey had recei(ed a diagno!i! of
!chi-oaffec"i(e di!order, men"al re"ar9 da"ion, or
o"her cogni"i(e di!order!D had a hi!"ory of !eriou!
ad(er!e reac"ion! "o "he roo!ed "rea"9 men"!D
had had only one !chi-ohrenic ei!odeD had a
hi!"ory of "rea"men" re!i!"ance, defined )y "he
er!i!"ence of !e(ere !ym"om! de!i"e ade>ua"e
"rial! of one of "he roo!ed "rea"men"! or rior
"rea"men" wi"h clo-aineD were regnan" or )rea!"9
feedingD or had a !eriou! and un!"a)le medical
condi"ion.
The !"udy wa! aro(ed )y "he in!"i"u"ional re9
(iew )oard a" each !i"e, and wri""en informed con9
!en" wa! o)"ained from "he a"ien"! or "heir legal
guardian!.
1210 n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
effec"i(ene!! of an"i!ycho"ic drug! in chronic !chi-ohrenia
interventions
5den"ical9aearing ca!ule! con"ained olan-a9
ine 6@yreEa, Eli .illy7 6<.% mg7, >ue"iaine 6&ero9
>uel, '!"ra@eneca7 6200 mg7, ri!eridone 60i!er9
dal, Jan!!en ,harmaceu"ica7 61.% mg7,
erhena-ine 6Trilafon, &chering9,lough, a" "he
"ime of "he !"udy7 6* mg7, or 6af"er January 20027
-ira!idone 6Oeo9 don, ,fi-er7 640 mg7. The
ac1aging wa! done )y Guin"ile!. The do!e of
medica"ion! wa! fleEi)le, ranging from one "o
four ca!ule! daily, and wa! )a!ed on "he !"udy
doc"orK! judgmen". 2(erla in "he admini!"ra"ion
of "he an"i!ycho"ic agen"! "ha" a"ien"! recei(ed
)efore !"udy en"ry wa! ermi""ed for "he fir!" four
wee1! af"er randomi-a"ion "o allow a gradual
"ran!i"ion "o !"udy medica"ion. #oncom9 i"an"
medica"ion! were ermi""ed "hroughou" "he "rial,
eEce" for addi"ional an"i!ycho"ic agen"!.
,a"ien"! had mon"hly (i!i"! wi"h !"udy doc"or!.
4ecau!e of roduc" la)eling, >ue"iaine and
-ira!idone are gi(en "wice daily and olan-aine,
erhena-ine, and ri!eridone once daily. To
ro9 "ec" )linding, half "he a"ien"! randomly
a!!igned "o erhena-ine, olan-aine, and
ri!eridone were a!!igned "o "wice9daily do!ing
and half "o once9 daily do!ing. To minimi-e
ini"ial !ide effec"!, a9 "ien"! a!!igned "o
>ue"iaine )egan "rea"men" )y recei(ing one 1009
mg ca!ule on day! 1 and 2, one "wice daily on
day +, and one for "he fir!" do!e of day 4. 'll
a"ien"! a!!igned "o "wice9daily do!ing recei(ed
fi(e iden"ical9aearing ca!ule! "o )egin
"rea"men". ,a"ien"! wi"h curren" "ardi(e dy!1ine9
!ia could enroll, )u" "he randomi-a"ion !cheme
re(en"ed "heir a!!ignmen" "o "rea"men" wi"h er9
hena-ine.
objectives and outcomes
:e hyo"he!i-ed "ha" "here would )e !ignifican"
difference! in "he o(erall effec"i(ene!! of olan-a9
ine, erhena-ine, >ue"iaine, ri!eridone, and
-ira!idone in "rea"ing !chi-ohrenia "ha" reflec"ed
(aria"ion! in efficacy and "olera)ili"y. The rimary
ou"come mea!ure wa! "he di!con"inua"ion of
"rea"9 men" for any cau!e, a di!cre"e ou"come
!elec"ed )e9 cau!e !"oing or changing
medica"ion i! a fre>uen" occurrence and major
ro)lem in "he "rea"men" of !chi-ohrenia. 5n
addi"ion, "hi! mea!ure in"egra"e! a"ien"!K and
clinician!K judgmen"! of efficacy, !afe9 "y, and
"olera)ili"y in"o a glo)al mea!ure of effec9
"i(ene!! "ha" reflec"! "heir e(alua"ion of
"heraeu"ic )enefi"! in rela"ion "o unde!ira)le
effec"!. The 1ey !econdary ou"come! were "he
!ecific rea!on! for "he di!con"inua"ion of
"rea"men" 6e.g., inefficacy or
in"olera)ili"y owing "o !ide effec"! !uch a! weigh"
gain, eE"rayramidal !ign!, or !eda"ion a! judged
)y "he !"udy doc"or7. 'ddi"ional !econdary
efficacy ou"come! included !core! on "he ,o!i"i(e
and Neg9 a"i(e &yndrome &cale 6,'N&&7 and "he
#linical Olo)al 5mre!!ion! 6#O57 &cale. ,'N&&
!core! can range from +0 "o 210, wi"h higher
!core! indica"9 ing more !e(ere !ychoa"hology.
&core! for "he #O5 &cale can range from 1 "o <,
wi"h higher !core! indica"ing grea"er !e(eri"y of
illne!!. &econdary !afe9 "y and "olera)ili"y
ou"come!, which were e(alua"ed a" mon"h! 1, +,
?, ;, 12, 1%, and 1*, included "he in9 cidence of
!eriou! ad(er!e e(en"!, "he incidence of ad(er!e
e(en"! during "rea"men", "he incidence of
neurologic !ide effec"!, and change! in weigh",
elec9 "rocardiograhic finding!, and la)ora"ory
analy"e!.
statistical analysis
0andomi-ed a"ien"! who recei(ed a" lea!" one
do!e of !"udy medica"ion made u "he in"en"ion9
"o9 "rea" oula"ion. Two hundred "hir"y9one
a"ien"! wi"h "ardi(e dy!1ine!ia were eEcluded
from random a!!ignmen" "o erhena-ine.
@ira!idone wa! add9 ed "o "he "rial af"er
aroEima"ely 40 ercen" of "he a"ien"! had )een
enrolled. #on!e>uen"ly, com9 ari!on! in(ol(ing
"he erhena-ine grou were limi"ed "o a"ien"!
wi"hou" "ardi(e dy!1ine!ia, and comari!on!
in(ol(ing "he -ira!idone grou were limi"ed "o
"he cohor" of a"ien"! who underwen"
randomi-a"ion af"er -ira!idone wa! added 6"he
-ira!idone cohor"7. 5n general, "he "rial had a !"a9
"i!"ical ower of *% ercen" "o iden"ify an a)!olu"e
difference of 12 ercen" in "he ra"e! of di!con"inu9
a"ion )e"ween "wo a"yical agen"!D howe(er, i"
had a !"a"i!"ical ower of <? ercen" for
comari!on! in(ol(ing erhena-ine and of %*
ercen" for com9 ari!on! in(ol(ing -ira!idone.
:e u!ed 3alanPMeier !ur(i(al cur(e! "o e!"i9
ma"e "he "ime "o "he di!con"inua"ion of "rea"men".
Trea"men" grou! were comared wi"h u!e of #oE
roor"ional9ha-ard! regre!!ion model!
2;
!"ra"i9
fied according "o !i"e, wi"h adju!"men" for whe"her
"he a"ien" had had an eEacer)a"ion of !chi-ohre9
nia in "he receding "hree mon"h! and "ardi(e dy!9
1ine!ia !"a"u! 6for model! eEcluding erhena9
-ine7. &i"e! wi"h 1% or fewer a"ien"! were
groued according "o "he !i"e!K heal"h care
!y!"em!.
The o(erall difference among "he olan-aine,
>ue"iaine, ri!eridone, and erhena-ine grou!
wa! e(alua"ed wi"h "he u!e of a "e!" wi"h +
degree! of freedom 6df 7. 5f "he difference wa!
!ignifican" a" a , (alue of le!! "han 0.0%, "he "hree
a"yical9drug
n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
1211
The new england journal of medicine
grou! were comared wi"h each o"her )y mean!
of !"e9down or clo!ed "e!"ing, wi"h a , (alue of
le!! "han 0.0% con!idered "o indica"e !"a"i!"ical
!ig9 nificance. Each grou wa! "hen comared
wi"h "he erhena-ine grou )y mean! of a
/och)erg ad9 ju!"men" for mul"ile
comari!on!.
+0
The !malle!" re!ul"ing , (alue wa!
comared wi"h a (alue of 0.01< 60.0% Q +7. The
-ira!idone grou wa! direc"ly com9 ared wi"h
"he o"her "hree a"yical9drug grou! and "he
erhena-ine grou wi"hin "he -ira!idone co9
hor" )y mean! of a /och)erg adju!"men" for four
airwi!e comari!on!. The !malle!" re!ul"ing ,
(al9 ue wa! comared wi"h a (alue of 0.01+ 60.0%
Q 47.
&ucce!!ful "rea"men" "ime wa! defined a! "he
num)er of mon"h! of "rea"men" during ha!e 1 in
which a"ien"! had a #O5 &cale !core of a" lea!"
+ 6mildly ill7 or a !core of 4 6modera"ely ill7 wi"h
an imro(emen" of a" lea!" "wo oin"! from
)a!eline. Trea"men" grou! were comared wi"h
u!e of ro9 or"ional9ha-ard! regre!!ion.
' !en!i"i(i"y analy!i! of "he #oE model for
"he di!con"inua"ion of "rea"men" for any cau!e
e(alua"9 ed "he effec"! of o"en"ially imor"an"
)a!eline co9 (aria"e! and "heir in"erac"ion wi"h
"he "rea"men" grou.
The ,'N&& "o"al !core! and #O5 &cale !core!
o(er "ime were comared among "he grou! wi"h
"he u!e of a miEed model including "he !ame
fiEed co(aria"e! a! for "he "ime "o di!con"inua"ion,
lu! )a!eline (alue, "ime, "he in"erac"ion )e"ween
"rea"9 men" and "ime, and "he in"erac"ion )e"ween
)a!e9 line (alue and "ime. Time wa! cla!!ified in"o
mon"h! 61, +, ?, ;, 12, 1%, and 1*7. The re!ul"!
of a!!e!!9 men"! made a" "he end of ha!e 1 were
a!!igned "o "he neE" in"er(al. The correla"ion of
"he reea"ed mea!ure! wi"hin each a"ien" wa!
modeled wi"h "he u!e of a random !u)jec"
in"erce" and an un9 !"ruc"ured co(ariance
ma"riE.
The !"udy wa! funded )y "he N5M/. The
harma9 ceu"ical comanie! who!e drug! were
included in "he !"udy dona"ed drug !ulie!, and
each ro(id9 ed ad(ice on "he do!e of i"! own
drugD "hey were o"herwi!e no" in(ol(ed in "he
de!ign of "he !"udy, analy!e!, or in"erre"a"ion of
re!ul"!. The manu9 !cri" wa! wri""en !olely )y
"he li!"ed au"hor!.
re!ul"!
!"udy a"ien"!D 14;+ a"ien"! were enrolled in "he
!"udy and randomly a!!igned "o "rea"men". 'll
da"a from one !i"e 6++ a"ien"!7 were eEcluded
)efore analy!i!, owing "o concern a)ou" "he
in"egri"y of da"a from "ha" !i"e )efore "he end of
"he !"udy and )efore un)linding. The mean modal
do!e! were 20.1 mg er day for olan-aine, 20.*
mg er day for er9 hena-ine, %4+.4 mg er day
for >ue"iaine, +.; mg er day for ri!eridone,
and 112.* mg er day for -ira!idone 6Ta)le 27.
&e(en"y9four ercen" of a9 "ien"! in "he
in"en"ion9"o9"rea" analy!i! 610?1 of
14+27 di!con"inued "heir a!!igned "rea"men" in
ha!e 1 )efore 1* mon"h! 6median, ?7.
discontinuation of treatment
The "ime "o "he di!con"inua"ion of "rea"men" for
any cau!e wa! longer in "he olan-aine grou
"han in "he >ue"iaine grou 6ha-ard ra"io, 0.?+D
,B0.0017, "he ri!eridone grou 6ha-ard ra"io, 0.<%D
,C0.0027, or "he erhena-ine grou 6ha-ard
ra"io, 0.<*D , C 0.0217 6Ta)le 27. /owe(er, "he
difference )e9 "ween "he olan-aine grou and "he
erhena-ine grou wa! no" !ignifican" af"er
adju!"men" for mul9 "ile comari!on! 6re>uired ,
(alue, R0.01<7. :i"h9 in "he cohor" of **; a"ien"!
who underwen" ran9 domi-a"ion af"er -ira!idone
wa! added "o "he "rial, "ho!e recei(ing olan-aine
had a longer in"er(al )e9 fore di!con"inuing
"rea"men" for any cau!e "han did "ho!e in "he
-ira!idone grou 6ha-ard ra"io,
0.<?D , C 0.02*7. /owe(er, "hi! difference wa!
no" !ignifican" af"er adju!"men" for mul"ile
comari9 !on! 6re>uired , (alue, R0.01+7.
The "ime "o "he di!con"inua"ion of "rea"men"
for lac1 of efficacy wa! longer in "he olan-aine
grou "han in "he erhena-ine grou 6ha-ard
ra"io, 0.4<D ,B0.0017, "he >ue"iaine grou 6ha-ard
ra"io, 0.41D ,B0.0017, "he ri!eridone grou
6ha-ard ra"io,
0.4%D ,B0.0017, or "he -ira!idone grou 6ha-ard
ra"io, 0.%;D , C 0.02?7, )u" "he difference
)e"ween "he olan-aine and -ira!idone grou!
wa! no" !ig9 nifican" af"er adju!"men" for mul"ile
comari!on! 6re>uired , (alue, R0.01+7 6Ta)le 27.
There were no !ignifican" difference! )e"ween
grou! in "ime un9 "il di!con"inua"ion owing "o
in"olera)le !ide effec"! 6, C 0.0%47. The "ime un"il
di!con"inua"ion owing "o "he a"ien"K! deci!ion
6i.e., "he a"ien" indeen9 den"ly cho!e "o !"o
"rea"men"7 wa! !imilar "o "ha"
for di!con"inua"ion for any cau!e 6Ta)le 27.
characteristics and disposition
of patients
Ta)le 1 !how! "he )a!eline demograhic and
clini9 cal charac"eri!"ic! of "he a"ien"!. Figure 1
deic"! "he enrollmen", randomi-a"ion, and
follow9u of
The dura"ion of !ucce!!ful "rea"men" wa! !ig9 nifican"ly longer
in "he olan-aine grou "han in "he >ue"iaine grou 6ha-ard ra"io,
0.%+D ,B0.0017, "he ri!eridone grou 6ha-ard ra"io, 0.?;D ,C0.0027,
or "he erhena-ine grou 6ha-ard ra"io, 0.<+D
1212 n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
effec"i(ene!! of an"i!ycho"ic drug! in chronic !chi-ohrenia
Table 1. Baseline Demographic and Clinical Characteristics of Randomized atients.!
"lanzapine #uetiapine Risperidone erphenazine $iprasidone Total
Characteristic %& ' (()* %& ' ((+* %& ' (,1* %& ' -)1*. %& ' 1/0* %& '
1,)1*
Demographic characteristics
'ge S yr 40.*T10.* 40.;T11.2 40.?T11.+ 40.0T11.1 40.1T11.0 40.?T11.1
&eE S no. 6U7
Male 244 6<+7 2%% 6<?7 2%+ 6<47 1;; 6<?7 12; 6<07 10*0 6<47
Female ;2 62<7 *2 6247 ** 62?7 ?2 6247 %? 6+07 +*0 62?7
0ace S no. 6U7V
:hi"e 1;? 6%*7 21+ 6?+7 204 6?07 1%2 6%*7 10; 6?07 *<4 6?07
4lac1 11; 6+%7 114 6+47 122 6+?7 ;+ 6+?7 ?% 6+?7 %1+ 6+%7
2"her 21 6?7 10 6+7 1% 647 1? 6?7 ; 6%7 <1 6%7
&ani!h, /i!anic, or .a"ino e"hnici"y S no. 6U7 42 6127 4* 6147 +* 6117 24 6;7 1* 6107 1<0 6127
Educa"ion S yr 12.2T2.2 12.1T2.4 12.0T2.2 12.1T2.1 12.0T2.% 12.1T2.+
Mari"al !"a"u! S no. 6U7
Married +? 6117 +4 6107 +< 6117 4+ 61?7 1< 6;7 1?< 6117
,re(iou!ly marriedW 10% 6+17 ;0 62<7 101 6+07 ?* 62?7 ?1 6++7 42% 62;7
Ne(er married 1;% 6%*7 21+ 6?+7 20+ 6?07 1%0 6%<7 10< 6%*7 *?* 6%;7
=nemloyed S no. 6U7X 2*1 6*%7 2<4 6*47 2** 6*?7 21; 6*%7 1%% 6*%7 121< 6*%7
EEacer)a"ion in re(iou! + mo S no. 6U7 ;0 62<7 *; 62?7 ;% 62*7 ?* 62?7 ?0 6+27 402 62*7
,'N&& "o"al !coreY <?.1T1*.2 <%.<T1?.; <?.4T1?.? <4.+T1*.1 <%.4T1*.? <%.<T1<.?
#linician9ra"ed #O5 !e(eri"y !core88 4.0T1.0 +.;T0.; 4.0T0.; +.;T1.0 +.;T0.; 4.0T0.;
sychiatric history
'ge a" 1!" "rea"men" for any )eha(ioral 24.1T;.0 2+.?T*.1 2+.<T;.+ 24.%T*.? 24.1T;.< 24.0T*.;
or emo"ional ro)lem S yr
Fear! !ince 1!" an"i!ycho"ic medica"ion 14.%T11.0 14.?T10.+ 14.*T10.< 1+.*T11.0 14.0T10.% 14.4T10.<
re!cri)ed
2C3D diagnosis in past 0 yr 4 no. %5*
Dere!!ion *? 62?7 *4 62%7 104 6+07 <1 62<7 ?0 6+27 40% 62*7
'lcohol deendence or alcohol a)u!e <4 6227 *1 6247 ;2 62<7 <4 62*7 +< 6207 +%* 62%7
Drug deendence or drug a)u!e *? 62?7 ;% 62*7 110 6+27 <4 62*7 %< 6+17 422 62;7
2)!e!!i(ePcomul!i(e di!order 10 6+7 22 6<7 21 6?7 12 6%7 * 647 <+ 6%7
2"her anEie"y di!order 44 61+7 4? 6147 %2 61%7 2; 6117 2* 61%7 1;; 6147
Baseline antipsychotic medications 4 no. %5*..
2lan-aine alone <* 62+7 ?; 6207 <? 6227 %* 6227 41 6227 +22 6227
Gue"iaine alone 24 6<7 1< 6%7 22 6?7 1% 6?7 1< 6;7 ;% 6<7
0i!eridone alone %< 61<7 %; 61*7 ?+ 61*7 ?4 62%7 +2 61<7 2<% 61;7
'ny com)ina"ion including olan-aine, >ue"ia9 +1 6;7 +2 6107 ++ 6107 21 6*7 * 647 ;% 6<7
ine, or ri!eridone
'll o"her! %2 61%7 %* 61<7 ?0 61*7 +0 6117 2; 61?7 22; 61?7
None ;4 62*7 102 6+07 *< 62?7 <+ 62*7 %* 6+17 414 62*7
Baseline medical diagnoses 4 no. %5*
Dia)e"e! 6"ye 1 or 27 +? 6117 40 6127 +2 6;7 2; 6117 1< 6;7 1%4 6117
/yerliidemia %? 61<7 44 61+7 42 6127 +? 6147 2? 6147 204 6147
/yer"en!ion ?* 6207 ?< 6207 ?+ 61*7 ?0 62+7 +1 61<7 2*; 6207
8 ,lu!Pminu! (alue! are mean! T&D. 4ecau!e of rounding, ercen"age! may no" !um "o 100. &#5D deno"e! &"ruc"ured #linical 5n"er(iew for D&M95L.
Z ,a"ien"! wi"h "ardi(e dy!1ine!ia were eEcluded from "he erhena-ine grou.
V 0ace wa! !elf9reor"ed. I2"herJ include! 'merican 5ndian or 'la!1a Na"i(e 6le!! "han 1 ercen" of a"ien"!7, '!ian 62 ercen"7, Na"i(e
/awaiian or o"her ,acific 5!lander 6le!! "han 1 ercen"7, and "wo or more race! 62 ercen"7. ,ercen"age! are )a!ed on "he num)er of a"ien"!
wi"h da"a a(aila)leA ++? in "he olan-aine grou, ++< in "he >ue"iaine grou, +41 in "he ri!eridone grou, 2?1 in "he erhena-ine grou,
and 1*+ in "he -ira!idone grou.
W Thi! ca"egory include! a"ien"! who were widowed, di(orced, or !eara"ed.
X ,ercen"age! are )a!ed on "he num)er of a"ien"! wi"h da"a a(aila)leA ++0 in "he olan-aine grou, +2* in "he >ue"iaine grou, ++? in "he
ri!9 eridone grou, 2%; in "he erhena-ine grou, and 1*2 in "he -ira!idone grou.
Y &core! on "he ,o!i"i(e and Nega"i(e &yndrome &cale 6,'N&&7 for !chi-ohrenia can range from +0 "o 210, wi"h higher !core! indica"ing
more !e(ere !ychoa"hology.
88 The #O5 !e(eri"y !core can range from 1 "o <, wi"h higher !core! indica"ing grea"er !e(eri"y of illne!!.
ZZ ,ercen"age! for )a!eline medica"ion! are )a!ed on "he num)er of a"ien"! wi"h da"a on concomi"an" medica"ion!A +++ in "he olan-aine
grou, +++ in "he >ue"iaine grou, +40 in "he ri!eridone grou, 2%; in "he erhena-ine grou, and 1*4 in "he -ira!idone grou.
n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
121+
The new england journal of medicine
1*;4 &creened
401 EEcluded
124 Did no" mee" !"udy cri"eria
10; Declined
++ Decided again!" changing
an"i!ycho"ic agen"
1+% /ad o"her rea!on!
14;+ =nderwen" randomi-a"ion
'll ++ a"ien"! from one !i"e
eEcluded )efore analy!i!
)ecau!e of concern a)ou"
in"egri"y of "he da"a
++? '!!igned "o 2?1 '!!igned "o ++< '!!igned "o +41 '!!igned "o 1*% '!!igned "o
olan-aine erhena-ine >ue"iaine ri!eridone -ira!idone
? Did no" "a1e drug 4 Did no" "a1e drug * Did no" "a1e drug * Did no" "a1e drug 2 Did no" "a1e drug
120 6+?U7 #omle"ed ?% 62%U7 #omle"ed ?0 61*U7 #omle"ed ** 62?U7 #omle"ed +* 621U7 #omle"ed
ha!e 1 ha!e 1 ha!e 1 ha!e 1 ha!e 1
210 6?4U7 Di!con"inued 1;2 6<%U7 Di!con"inued 2?; 6*2U7 Di!con"inued 24% 6<4U7 Di!con"inued 14% 6<;U7 Di!con"inued
olan-aine erhena-ine >ue"iaine ri!eridone -ira!idone
4* For lac1 of efficacy ?% For lac1 of efficacy ;2 For lac1 of efficacy ;1 For lac1 of efficacy 44 For lac1 of efficacy
?2 2wing "o in"oler9 40 2wing "o in"oler9 4; 2wing "o in"oler9 +4 2wing "o in"oler9 2* 2wing "o in"oler9
a)ili"y a)ili"y a)ili"y a)ili"y a)ili"y
<* 2wing "o a"ien"K! << 2wing "o a"ien"K! 10; 2wing "o a"ien"K! 101 2wing "o a"ien"K! ?+ 2wing "o a"ien"K!
deci!ion deci!ion deci!ion deci!ion deci!ion
22 For o"her rea!on! 10 For o"her rea!on! 1; For o"her rea!on! 1; For o"her rea!on! 10 For o"her rea!on!
++0 5ncluded in analy!i!
2%< 5ncluded in analy!i! +2; 5ncluded in analy!i! +++ included in analy!i! 1*+ 5ncluded in analy!i!
6igure 1. 7nrollment and "utcomes.
,a"ien"! wi"h "ardi(e dy!1ine!ia were no" a!!igned "o erhena-ine. @ira!idone wa! added "o "he !"udy af"er aroEima"ely 40 ercen"
of a"ien"! had )een enrolled.
, C0.01+7 and wa! !ignifican"ly longer in "he
ri!eri9 done grou "han in "he >ue"iaine grou
6ha-ard ra"io, 0.<<D , C 0.0217.
adjustment of outcomes for covariates
'n eElora"ory analy!i! iden"ified "he following
redic"or! of an earlier "ime "o di!con"inua"ionA
higher )a!eline ,'N&& !core 6, C 0.0017,
younger age 6,B0.0017, longer dura"ion !ince "he
fir!" u!e of an"i!ycho"ic medica"ion 6,C0.0%<7,
and "he an9 "i!ycho"ic drug "a1en )efore !"udy
en"ry 6,C0.0017. 4a!eline an"i!ycho"ic agen"!
were groued in"o !iE ca"egorie! 6Ta)le 17.
,a"ien"! recei(ing olan-aine or ri!eridone
)efore enrollmen" !"ayed in ha!e 1
of "he "rial longer "han "ho!e "a1ing no
an"i!ycho"9 ic agen"!, "ho!e "a1ing com)ina"ion
"rea"men"!, or "ho!e recei(ing a !ingle
an"i!ycho"ic agen" eEclud9 ing olan-aine,
>ue"iaine, or ri!eridoneD air9 wi!e ha-ard
ra"io! ranged from 0.?* 6,B0.0017 "o
0.*0 6,B0.027. No in"erac"ion! wi"h "rea"men"
grou were !ignifican" a" a , (alue of le!! "han
0.10. 'f"er adju!"men" for "he!e redic"or! of
di!con"inua"ion, "he re!ul"! of "rea"men"9grou
comari!on! were !imilar "o "he rimary re!ul"!.
efficacy measures
To"al ,'N&& !core! imro(ed o(er "ime in all
grou!
6Fig. 27. The miEed model re(ealed !ignifican"
(ari9
1214 n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
effec"i(ene!! of an"i!ycho"ic drug! in chronic !chi-ohrenia
a"ion in "rea"men" effec"! o(er "ime 6, C 0.0027.
5m9 ro(emen" wa! ini"ially grea"e!" in "he
olan-aine grou, )u" i"! ad(an"age dimini!hed
o(er "ime. The a""ern of change in "he !core! for
"he #O5 &cale wa! !imilar "o "ha" for "he ,'N&&
!core! 6, C 0.004 for "he in"erac"ion )e"ween
"rea"men" and "ime7.
adverse events
The ra"e! of ad(er!e e(en"! and !ide effec"! are
li!"9 ed in Ta)le +. Fewer a"ien"! in "he olan-aine
grou "han in "he o"her four grou! were
ho!i"ali-ed for an eEacer)a"ion of !chi-ohrenia
611 ercen" (!. 1% "o 20 ercen", ,B0.0017. 'f"er
adju!"men" for "he differen" dura"ion! of
"rea"men", "he olan-aine grou had a ri!1 ra"io
for ho!i"ali-a"ion of 0.1< er er!on9year of
"rea"men", a! comared wi"h ri!1 ra"io! of 0.+0
"o 0.44 in "he o"her grou!.
The ra"e! of "rea"men" di!con"inua"ion due "o
in"olera)le !ide effec"! differed )e"ween "rea"men"!
6,C 0.047. 0i!eridone had "he lowe!" ra"e 610
er9 cen"7, and olan-aine had "he highe!" ra"e 61*
er9 cen"7. Moreo(er, more a"ien"! di!con"inued
olan9 -aine owing "o weigh" gain or me"a)olic
effec"! 6; ercen" (!. 1 ercen" "o 4 ercen" wi"h
"he o"her four drug!, ,B0.0017 and more a"ien"!
di!con"in9 ued erhena-ine owing "o
eE"rayramidal effec"! 6* ercen" (!. 2 ercen" "o
4 ercen", , C 0.0027.
,a"ien"! in "he olan-aine and >ue"iaine
grou! had lower ra"e! of in!omnia 61? and 1*
ercen", re9 !ec"i(ely7 "han did a"ien"! in "he
o"her grou! 624 ercen" in "he ri!eridone grou,
2% ercen" in "he erhena-ine grou, and +0
ercen" in "he -ira!i9 done grou7. Gue"iaine
wa! a!!ocia"ed wi"h a high9 er ra"e of
an"icholinergic effec"! "han were "he o"her drug!
6+1 ercen" (!. 20 "o 2% ercen", ,B0.0017.
Neurologic Side Effects
There were no !ignifican" difference! among "he
grou! in "he incidence of eE"rayramidal !ide ef9
fec"!, a1a"hi!ia, or mo(emen" di!order! a!
reflec"ed )y ra"ing9!cale mea!ure! of !e(eri"y.
eight !ain and Meta"olic
Changes
,a"ien"! in "he olan-aine grou gained more
weigh" "han a"ien"! in any o"her grou, wi"h an
a(9 erage weigh" gain of 2 l) 60.; 1g7 er mon"h.
' larger roor"ion of a"ien"! in "he olan-aine
grou "han in "he o"her grou! gained < ercen" or
more of "heir )a!eline )ody weigh" 6+0 ercen" (!.
< "o 1? ercen", ,B0.0017.
2lan-aine had effec"! con!i!"en" wi"h "he o9
"en"ial de(elomen" of "he me"a)olic !yndrome
and
wa! a!!ocia"ed wi"h grea"er
increa!e! in glyco!yla"9 ed
hemoglo)in, "o"al chole!"erol,
and "riglyceride! af"er
randomi-a"ion "han "he o"her
!"udy drug!, e(en af"er
adju!"men" for "he dura"ion of
"rea"9 men". @ira!idone wa! "he
only !"udy drug a!!oci9 a"ed
wi"h imro(emen" in each of
"he!e me"a)olic (aria)le!. 2nly
ri!eridone wa! a!!ocia"ed wi"h
a !u)!"an"ial increa!e in
rolac"in le(el!.
#ther
$otential
%d&erse
E&ents
There were no !u)!"an"ially
differen" effec"! of "he
medica"ion! on "he correc"ed
GT in"er(al on elec9
"rocardiograhy, and "or!ade!
de oin"e! did no" de(elo in
any a"ien"!. There were no
!ignifican" difference! among
"he grou! in "he incidence of
new ca"arac"!. There were no
!ignifican" difference! among "he
grou! in "he ra"e! of !uicide
a""em"! or !uicidal idea"ion
reor"ed a! !eriou! ad(er!e
e(en"!.
concomitant medications
There were few !u)!"an"ial difference! among "he
grou! in "he ra"e! or "ye! of medica"ion! added
during "he !"udy. ,a"ien"! in "he olan-aine and
ri!9 eridone grou! were "he lea!" li1ely "o ha(e
anEio9 ly"ic agen"! added 6; and 10 ercen",
re!ec"i(ely, (!. 14 "o 1% ercen"7. Fewer a"ien"!
recei(ing >ue9 "iaine were re!cri)ed
an"icholinergic drug! 6+ er9 cen" (!. * "o 10
ercen"7.
di!cu!!ion
'll !econd9genera"ion an"i!ycho"ic drug! were in9
cluded in ha!e 1 of "hi! !"udy eEce" ariira-ole
6which wa! aro(ed )y "he FD' in No(em)er
20027 and clo-aine, which wa! included in ha!e
2 for a"ien"! who di!con"inued ha!e 1 of
"rea"men" owing "o lac1 of efficacy of "he a!!igned
drug. 'l9 "hough haloeridol i! "he fir!"9
genera"ion agen" mo!" commonly u!ed for
comari!on, we cho!e "o u!e erhena-ine
)ecau!e of i"! lower o"ency and modera"e !ide9
effec" rofile.
+1
2nly a minori"y of a"ien"! in each grou "oo1
"heir a!!igned drug for "he dura"ion of ha!e 1
6ra"e! of di!con"inua"ion ranged from ?4 "o *2
ercen"7. Thi! ou"come indica"e! "ha"
an"i!ycho"ic drug!, "hough effec"i(e, ha(e
!u)!"an"ial limi"a"ion! in "heir effec"i(ene!! in
a"ien"! wi"h chronic !chi-o9 hrenia. 'l"hough
"he ra"e! of di!con"inua"ion may ha(e )een
increa!ed )y "he fac" "ha" a"ien"! were
ar"icia"ing in a )linded, con"rolled "rial, "he ra"e!
are generally con!i!"en" wi"h "ho!e re(iou!ly o)9
n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
121%
Table -. "utcome 8easures of 7ffectiveness in the 3ntention9to9Treat opulation.!
"lanzapine #uetiapine Risperidone erphenazine $iprasidone
"utcome %& ' ((1* %& ' (-:* %& ' (((* %& ' -0+*. ;alue< %& '
1/(*= Dose>
Mean modal do!e S mg er day["o"al no. of a"ien"! 20.1[+12 %4+.4[+0; +.;[+0% 20.*[24% 112.*[1?%
MaEimal do!e recei(ed S no. of a"ien"! 6U7 124[+12 6407 1+<[+0; 6447 122[+0% 6407 ;*[24% 6407 B0.001 *0[1?% 64*7
Discontinuation of treatment for any cause
Di!con"inua"ion S no. of a"ien"! 6U7 210 6?47 2?; 6*27 24% 6<47 1;2 6<%7 14% 6<;7
3alanPMeier "ime "o di!con"inua"ion S mo
Median 6;%U #57 ;.2 6?.;P12.17 4.? 6+.;P%.%7 4.* 64.0P?.17 %.? 64.%P?.+7 +.% 6+.1P%.47
#oE9model "rea"men" comari!on!Y
2lan-aine
/a-ard ra"io 6;%U #57 0.?+ 60.%2P0.<?7 0.<% 60.?2P0.;07 0.<* 60.?+P0.;?7 0.00488 0.<? 60.?0P0.;<7
, (alue B0.00188 0.00288 0.021 0.02*
Gue"iaine
/a-ard ra"io 6;%U #57 1.1; 60.;;P1.427 1.14 60.;+P1.+;7 1.01 60.*1P1.2<7
, (alue 0.0? 0.21 0.;4
0i!eridone
/a-ard ra"io 6;%U #57 1.00 60.*2P1.2+7 0.*; 60.<1P1.147
, (alue 0.;; 0.+?
,erhena-ine
/a-ard ra"io 6;%U #57 0.;0 60.<0P1.1?7
, (alue 0.4+
Discontinuation of treatment for lack of efficacy
Di!con"inua"ion S no. of a"ien"! 6U7 4* 61%7 ;2 62*7 ;1 62<7 ?% 62%7 44 6247
3alanPMeier "ime "o di!con"inua"ion S mo
2%"h ercen"ile 6;%U #57 SZZ ?.0 64.%P*.07 ?.0 64.4P;.07 ?.1 64.%P;.17 ?.; 6+.2P12.17
#oE9model "rea"men" comari!on!Y
2lan-aine
/a-ard ra"io 6;%U #57 0.41 60.2;P0.%<7 0.4% 60.+2P0.?47 0.4< 60.+1P0.<07 B0.00188 0.%; 60.+<P0.;+7
, (alue B0.00188 B0.00188 B0.00188 0.02?
Gue"iaine
, (alue 0.4; 0.4< 0.?;
0i!eridone
, (alue 0.%; 0.;+
,erhena-ine
, (alue 0.44
Discontinuation of treatment o?ing to intolerability<<
Di!con"inua"ion S no. 6U7 ?2 61;7 4; 61%7 +4 6107 40 61?7 2* 61%7
#oE9model "rea"men" comari!on!Y
0i!eridone
/a-ard ra"io 6;%U #57 0.?2 60.41P0.;%7 0.?% 60.42P1.007 0.?0 60.+?P0.;*7 0.0%4 0.<; 60.4?P1.+<7
, (alue 0.02< 0.0%1 0.04+ 0.41
2lan-aine
, (alue 0.*4 0.4; 0.2*
Gue"iaine
, (alue 0.;< 0.*<
,erhena-ine
, (alue 0.1;
The
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on May
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er!onal
u!e only.
No o"her
u!e!
wi"hou"
ermi!!io
n.
Ma!!ac
Medica
&ocie"y.
atient@s decision to discontinue treatment==
Di!con"inua"ion S no. 6U7 <* 6247 10; 6++7 101 6+07 << 6+07 ?+ 6+47
3alanPMeier "ime "o di!con"inua"ion S mo
2%"h ercen"ile 6;%U #57 12.+ 6*.0P1<.*7 4.; 6+.1P<.07 4.% 6+.1P*.*7 ?.2 64.<P*.17 +.4 6+.0P?.17
#oE9model "rea"men" comari!on!Y
2lan-aine
/a-ard ra"io 6;%U #57 0.%? 60.42P0.<%7 0.?< 60.%0P0.;07 0.<0 60.%0P0.;*7 0.0+488 0.?+ 60.4+P0.;+7
, (alue B0.00188 0.00*88 0.0+? 0.01*
Gue"iaine
, (alue 0.21 0.4? 0.?+
0i!eridone
, (alue 0.;% 0.21
,erhena-ine
, (alue 0.2<
Duration of successful treatment>>
3alanPMeier "ime "o di!con"inua"ion S mo
Median 6;%U #57 + 62P%7 1 60P17 1 60P17 1 61P27 1 60P17
#oE9model "rea"men" comari!on!Y
2lan-aine
/a-ard ra"io 6;%U #57 0.%+ 60.4+P0.?<7 0.?; 60.%%P0.*<7 0.<+ 60.%<P0.;+7 B0.00188 0.<% 60.%*P0.;47
, (alue B0.00188 0.00288 0.01+88 0.01<
Gue"iaine
/a-ard ra"io 6;%U #57 1.+0 61.04P4.?+7 1.2* 61.00P1.?47 1.0? 60.*%P1.++7
, (alue 0.0288 0.0% 0.?1
0i!eridone
, (alue 0.<2 0.<4
,erhena-ine
, (alue 0.2%
8 #5 deno"e! confidence in"er(al.
Z ,a"ien"! wi"h "ardi(e dy!1ine!ia were eEcluded from "he erhena-ine grou.
V The o(erall , (alue i! for "he comari!on of olan-aine, >ue"iaine, ri!eridone, and erhena-ine wi"h "he u!e of a + df "e!" from a #oE model for !ur(i(al ou"come!, eEcluding
a"ien"! wi"h "ardi(e dy!1ine!ia. 5f "he difference among "he grou! wa! !ignifican" a" a , (alue of le!! "han 0.0%, "he "hree a"yical agen"! were comared wi"h each o"her )y mean! of
!"e9down or clo!ed "e!"ing "o iden"ify !ignifican" difference! 6,B0.0%7 )e"ween grou!. Each a"yical agen" wa! "hen comared wi"h erhena-ine )y mean! of a /och)erg adju!"men".
The !mall9 e!" , (alue for "he erhena-ine grou wa! comared wi"h a (alue of 0.01< 60.0% Q +7.
W &"a"i!"ical analy!e! in(ol(ing "he -ira!idone grou were confined "o "he cohor" of a"ien"! who underwen" randomi-a"ion af"er -ira!idone wa! added "o "he !"udy, wi"h "he u!e of a
/och)erg adju!"men" for four airwi!e comari!on!. The !malle!" , (alue wa! comared wi"h a (alue of 0.01+ 60.0% Q 47.
X The modal do!e and ercen"age! of a"ien"! "a1ing "he maEimal do!e are )a!ed on "he num)er of a"ien"! wi"h da"a on "he do!e. 5nforma"ion on do!e wa! no" a(aila)le for !ome a9
"ien"! who droed ou" early. The , (alue! for "he ercen"age of a"ien"! reaching "he maEimal do!e were calcula"ed wi"h "he u!e of a 4 df "e!" comaring all "rea"men" grou! from a
,oi!!on regre!!ion accoun"ing for differen"ial eEo!ure "ime!, and adju!"ing for whe"her "he a"ien" had had an eEacer)a"ion in "he receding "hree mon"h!.
Y For airwi!e comari!on! of "rea"men" grou!, #oE9model ha-ard ra"io! of le!! "han 1 indica"e a grea"er "ime "o "he di!con"inua"ion of "he fir!" "rea"men" li!"ed.
88 , (alue i! !"a"i!"ically !ignifican".
ZZ The 3alanPMeier 2%"h ercen"ile for di!con"inua"ion owing "o lac1 of efficacy could no" )e e!"ima"ed for olan-aine )ecau!e of "he low e(en" ra"e!.
VV The 3alanPMeier 2%"h ercen"ile for di!con"inua"ion owing "o in"olera)ili"y could no" )e e!"ima"ed )ecau!e of "he low e(en" ra"e!.
WW Thi! ca"egory include! deci!ion! made )y )o"h a"ien"! and "heir ad(oca"e!.
XX &ucce!!ful "rea"men" wa! defined )y a #O5 !e(eri"y !core of a" lea!" + 6mildly ill7 or )y a !core of 4 6modera"ely ill7 wi"h an imro(emen" of a" lea!" "wo oin"! from )a!eline.
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The New England Journal of Medicine
Downloaded from nejm.org on May 12, 2014. For er!onal u!e only. No o"her u!e! wi"hou" ermi!!ion.
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The new england journal of medicine
!er(ed.
%
:i"hin "hi! limi"ed range of effec"i(ene!!, "he olan-aine grou had
"he lowe!" ra"e of di!con9 "inua"ion, which migh" lead one "o con!ider olan9
-aine "he mo!" effec"i(e of "he medica"ion! !"ud9 ied. 5"! aaren" !uerior
efficacy i! al!o indica"ed )y "he grea"er reduc"ion in !ychoa"hology, longer
dura"ion of !ucce!!ful "rea"men", and lower ra"e of ho!i"ali-a"ion! for an
eEacer)a"ion of !chi-ohre9 nia. The re!ul"! for "he o"her !econd9genera"ion
an"i!ycho"ic agen"! and "he rere!en"a"i(e con9 (en"ional drug,
erhena-ine, were !imilar in mo!" re!ec"!. 5" i! imor"an" "o no"e "ha" "he
difference! )e"ween olan-aine and erhena-ine were mod9 era"e.
'l"hough "here were no !ignifican" differ9 ence! in "he "ime un"il
di!con"inua"ion owing "o in"olera)le !ide effec"!, "here were difference! in
ra"e!. Moreo(er, olan-aine wa! a!!ocia"ed wi"h grea"er increa!e! in weigh"
and indeEe! of gluco!e and liid me"a)oli!m "han "he o"her "rea"men"!.
Do!e could ha(e )een a fac"or in "he erformance of "he (ariou! agen"!
!"udied. The do!e range! a9 ro(ed )y "he FD' for >ue"iaine and
-ira!idone may )e )elow "heir o"imal "heraeu"ic do!e!, and "he
recommended do!e! of ri!eridone 6? mg er day or le!!7, in"ended "o limi"
eE"rayramidal !ym"om!, may no" encoma!! i"! full "heraeu9 "ic
range.
+2,++
/owe(er, "he do!e range! we u!ed were )a!ed on informa"ion
from "he manufac"urer of each medica"ion lu! 1nowledge of clinical rac9
"ice a""ern!. Moreo(er, "he a(erage re!cri)ed do!9 e! of "he!e drug! in "he
=ni"ed &"a"e! for a"ien"! wi"h !chi-ohrenia during "he eriod in which "he
!"udy wa! conduc"ed 614 mg of olan-aine er day,
+.* mg of ri!eridone er day, +** mg of >ue"ia9 ine er day, and 12% mg
of -ira!idone er day7 were generally !imilar "o "he one! we u!ed.
+4
The
fac" "ha" a higher roor"ion of a"ien"! a!!igned "o >ue"iaine and
-ira!idone recei(ed "he maEimal do!e allowed in "he !"udy !ugge!"! "ha"
"he!e agen"! are ei"her le!! effec"i(e or re>uire higher do!e! 6Ta9 )le 27. The
do!e range of erhena-ine wa! cho!en "o minimi-e "he o"en"ial for
eE"rayramidal !ym9 "om! "ha" may ha(e )ia!ed re(iou! comari!on! of
fir!"9 and !econd9genera"ion drug!.
4,<,+1
The u!e of low9do!e erhena-ine aear! "o ha(e dimini!hed "he
fre>uency of eE"rayramidal !ide effec"! in a"ien"! who recei(ed "he fir!"9
gener9 a"ion drug. 5n con"ra!" "o re(iou! !"udie!,
+%
"he ro9 or"ion of a"ien"!
wi"h eE"rayramidal !ym"om! did no" differ !ignifican"ly among "ho!e who
re9 cei(ed fir!"9genera"ion and !econd9genera"ion drug! in our !"udy. De!i"e
"hi! finding, more a"ien"! di!9
6igure - %facing page*. "utcome 8easures of 7ffec9 tiveness.
The num)er of a"ien"! included a" each a!!e!!men" "ime oin" declined o(er
"ime. E!"ima"e! are from a miEed model, which a!!umed "ha" da"a were mi!!ing a"
random. &core! for "he ,'N&& and #O5 &cale were de"ermined a" !"udy en"ry and
1, +, ?, ;, 12, 1%, and 1* mon"h! af"er ran9 domi-a"ion. &core! for "he ,'N&& can
range from +0 "o
210, wi"h higher !core! indica"ing more !e(ere !ycho9 a"hology. &core! for "he
#O5 &cale can range from 1 "o <, wi"h higher !core! indica"ing a grea"er !e(eri"y of
illne!!. 'naly!e! in(ol(ing "he -ira!idone grou were limi"ed "o "he cohor" of
a"ien"! who underwen" randomi-a"ion af"er "he addi"ion of -ira!idone "o "he
!"udy 6"he -ira!idone cohor"7. Thu!, "he , (alue for "he o(erall in"erac"ion )e9
"ween "ime and "rea"men" eEclude! "he -ira!idone grou and i! gi(en !eara"ely
for "he -ira!idone cohor".
con"inued erhena-ine "han o"her medica"ion! ow9 ing "o
eE"rayramidal effec"!.
'! in o"her !"udie!, we found "ha" ri!eridone wa! a!!ocia"ed wi"h
hyerrolac"inemia and olan9 -aine wa! a!!ocia"ed wi"h !u)!"an"ial
weigh" gain in addi"ion "o ad(er!e change! in gluco!e and liid
me"a)oli!m S all fea"ure! of "he me"a)olic !yn9 drome. #oncern!
a)ou" o"en"ial rolonga"ion of "he correc"ed GT in"er(al wi"h
-ira!idone and of ca"arac"! wi"h >ue"iaine were no" reali-ed in "hi!
!"udy.
:e u!ed )road inclu!ion and minimal eEclu9 !ion cri"eria and
allowed "he enrollmen" of a"ien"! wi"h coeEi!"ing condi"ion! and "ho!e
who were "a19 ing o"her medica"ion!. The !"udy wa! conduc"ed in a
(arie"y of clinical !e""ing! in which eole wi"h !chi-ohrenia are
"rea"ed. The!e Ireal9worldJ fea9 "ure! of "he !"udy, which were
in"ended "o ma1e "he re!ul"! widely alica)le, may accoun" for "he
dif9 ference! in re!ul"! )e"ween "hi! and re(iou! !"ud9 ie! comaring
fir!"9 and !econd9genera"ion an"i9 !ycho"ic agen"!.
5n !ummary, a"ien"! wi"h chronic !chi-ohre9 nia in "hi! !"udy
di!con"inued "heir an"i!ycho"ic !"udy medica"ion! a" a high ra"e,
indica"ing !u)9 !"an"ial limi"a"ion! in "he effec"i(ene!! of "he drug!.
:i"hin "hi! limi"ed range of effec"i(ene!!, olan-a9 ine aeared "o )e
more effec"i(e "han "he o"her drug! !"udied, and "here were no
!ignifican" dif9 ference! in effec"i(ene!! )e"ween "he con(en"ional drug
erhena-ine and "he o"her !econd9genera9 "ion drug!. There were
no !ignifican" difference! among "he drug! in "he "ime un"il
di!con"inua"ion of "rea"men" owing "o in"olera)le !ide effec"!. /ow9
e(er, olan-aine wa! a!!ocia"ed wi"h grea"er weigh"
The New England Journal of Medicine
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121* n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
effec"i(ene!! of an"i!ycho"ic drug! in chronic !chi-ohrenia
0.1
0.1
ri!eridone, and erhena-ine
2lan-aine 6NC++07 0i!eridone 6NC+++7 @ira!idone 6NC1*+7
,erhena-ine 6NC2%<7 Gue"iaine 6NC+2;7
A
1.0
0.;
0.*
0.<
0.?
0.%
0.4
0.+
0.2
, B 0.001 for olan-aine (!. >ue"iaine
0.0
0 + ? ; 12 1% 1*
Time to Discontinuation for Any Cause %mo*
B
1.0
0.;
0.*
0.<
0.?
0.%
0.4
0.+
0.2
, B 0.001 for olan-aine (!. >ue"iaine,
0.0
0 + ? ; 12 1% 1*
Time to Discontinuation for Back of 7fficacy %mo*
C
1.0
0.;
0.*
0.<
0.?
0.%
0.4
0.+
0.2
0.1
0.0
0 + ? ; 12 1% 1*
Time to Discontinuation "?ing to
3ntolerability %mo*
D
1.0
0.;
0.*
0.<
0.?
0.%
0.4
0.+
0.2
0.1
, B 0.001 for olan-aine (!. >ue"iaine
, C 0.00* for olan-aine (!. ri!eridone
0.0
0 + ? ; 12 1% 1*
Time to Discontinuation "?ing to
atient@s Decision %mo*
7
0
\2
\4
\?
\*
\10 , C 0.002 for "ime9)y9"rea"men"
in"erac"ion
, C 0.0?% for -ira!idone cohor"
\12
0 + ? ; 12 1% 1*
6
0.0
\0.1
\0.2
\0.+
\0.4
\0.%
\0.?
, C 0.004 for "ime9)y9
"rea"men" in"erac"ion
, C 0.01< for -ira!idone cohor"
\0.<
0 + ? ; 12 1% 1*
, C 0.002 for olan-aine (!. ri!eridone
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The new england journal of medicine
Table (. "utcome 8easures of 2afety among Randomized atients.
"lanzapine #uetiapine Risperidone erphenazine $iprasidone
"utcome %& ' (()* %& ' ((+* %& ' (,1* %& ' -)1*! %& ' 1/0* ;alue.
Eospitalization for eFacerbation of schizophrenia
/o!i"ali-ed a"ien"! S no. 6U7 +* 6117 ?* 6207 %1 61%7 41 61?7 ++ 61*7 B0.001
No. of ho!i"ali-a"ion!["o"al er!on9yr of eEo!ure 4%[2%< *0[1*+ ?4[210 %4[1?1 40[100
0i!1 ra"io 0.1< 0.44 0.+0 0.++ 0.40
Adverse events 4 no. %5*
'ny !eriou! ad(er!e e(en" +2 6107 +2 6;7 ++ 6107 2; 6117 1; 6107 0.4<
&uicide a""em" 2 6B17 1 6B17 2 6B17 1 6B17 1 6B17 0.;;
&uicidal idea"ion 1 6B17 2 6B17 4 617 + 617 2 617 0.4;
'ny modera"e or !e(ere ad(er!e e(en" iden"ified )y 2+% 6<07 220 6?%7 2+2 6?*7 1<0 6?%7 11; 6?47 0.14
!y!"ema"ic in>uiry
5n!omnia %% 61?7 ?2 61*7 *+ 6247 ?? 62%7 %? 6+07 B0.001
/yer!omnia, !leeine!! 104 6+17 10+ 6+17 ;? 62*7 <4 62*7 4% 6247 0.1*
=rinary he!i"ancy, dry mou"h, con!"ia"ion <; 6247 10% 6+17 *4 62%7 %< 6227 +< 6207 B0.001
Decrea!ed !eE dri(e, arou!al, a)ili"y "o reach orga!m ;1 62<7 ?; 6207 ;1 62<7 ?4 62%7 +% 61;7 0.%;
Oynecoma!"ia, galac"orrhea < 627 ? 627 14 647 4 627 ? 6+7 0.1%
Men!"rual irregulari"ie!V 11 6127 % 6?7 1? 61*7 < 6117 * 6147 0.1<
5ncon"inence, noc"uria 1* 6%7 1% 647 2% 6<7 ? 627 10 6%7 0.04
2r"ho!"a"ic fain"ne!! +1 6;7 +* 6117 +< 6117 2; 6117 24 61+7 0.0*
'ny modera"e or !e(ere !on"aneou!ly reor"ed 122 6+?7 11+ 6+47 12+ 6+?7 <; 6+07 ?% 6+%7 0.10
ad(er!e e(en"
&eurologic effects 4 no.Gtotal no. %5*=
'5M& glo)al !e(eri"y !core ]2 +2[2+? 6147 +0[2+? 61+7 +*[2+* 61?7 41[2+< 61<7 1*[12? 6147 0.2+
4arne! '1a"hi!ia 0a"ing &cale glo)al !core ]+ 1%[2;0 6%7 1?[+0% 6%7 20[2;2 6<7 1?[241 6<7 14[1%* 6;7 0.24
&im!on P 'ngu! EE"rayramidal &ign! &cale mean 2+[2;? 6*7 12[2;* 647 2+[2;2 6*7 1%[24+ 6?7 ?[1%2 647 0.4<
!core ]1
Discontinuation of treatment o?ing to intolerability 4 no. 5
Di!con"inua"ion ?2 61*7 4; 61%7 +4 6107 40 61%7 2* 61%7 0.04
:eigh" gain or me"a)olic effec"! +1 6;7 12 647 ? 627 + 617 ? 6+7 B0.001
EE"rayramidal effec"! * 627 10 6+7 11 6+7 22 6*7 < 647 0.002
&eda"ion < 627 ; 6+7 + 617 < 6+7 0 0.10
2"her effec"! 1? 6%7 1* 6%7 14 647 * 6+7 1% 6*7 0.1?
Height change from baseline to last observation>
:eigh" gain ^<U S no.["o"al no. 6U7 ;2[+0< 6+07 4;[+0% 61?7 42[+00 6147 2;[24+ 6127 12[1?1 6<7 B0.001
:eigh" change S l)
Mean T&E ;.4T0.; 1.1T0.; 0.*T0.; \2.0T1.1 \1.?T1.1 B0.001
Median < 1 0 \1 \2
0ange \14 "o 42 \2% "o 2% \24 "o 24 \2; "o 22 \24 "o 1*
:eigh" change S l)[mo of "rea"men"
Mean T&E 2.0T0.+ 0.%T0.2 0.4T0.+ \0.2T0.2 \0.+T0.+ B0.001
Median 0.* 0.1 0.0 \0.1 \0.+
0ange \1.4 "o ;.% \4.4 "o ?.+ \4.? "o %.< \4.; "o 4.0 \%.+ "o %.;
Change from baseline in laboratory valuesI
4lood gluco!e S mg[dl
Mean T&E 1%.0T2.* ?.*T2.% ?.<T2.0 %.2T2.0 2.+T+.;
Median <.0 4.+ %.% 1.% 2.%
EEo!ure9adju!"ed mean T&E 1+.<T2.% <.%T2.% ?.?T2.% %.4T2.* 2.;T+.4 0.%;
Olyco!yla"ed hemoglo)in S U
Mean T&E 0.41T0.0; 0.0%T0.0% 0.0*T0.04 0.10T0.0? \0.10T0.14
Median 0.20 0.10 0.0% 0.0% 0.10
EEo!ure9adju!"ed mean T&E 0.40T0.0< 0.04T0.0* 0.0<T0.0* 0.0;T0.0; 0.11T0.0; 0.01
#hole!"erol S mg[dl
Mean T&E ;.<T2.1 %.+T2.1 \2.1T1.; 0.%T2.+ \;.2T%.2
Median *.% +.% \+.0 0.% \1.0
EEo!ure\adju!"ed mean T&E ;.4T2.4 ?.?T2.4 \1.+T2.4 1.%T2.< \*.2T+.2 B0.001
Triglyceride! S mg[dl
Mean T&E 42.;T*.4 1;.2T10.? \2.?T?.+ *.+T11.% \1*.1T;.4
Median ++.% 1<.% +.0 2.0 \<.0
EEo!ure9adju!"ed mean T&E 40.%T*.; 21.2T;.2 \2.4T;.1 ;.2T10.1 \1?.%T12.2 B0.001
1220 n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
effec"i(ene!! of an"i!ycho"ic drug! in chronic !chi-ohrenia
Table (. %Continued.*
"lanzapine #uetiapine Risperidone erphenazine $iprasidone
"utcome %& ' (()* %& ' ((+* %& ' (,1* %& ' -)1*! %& ' 1/0* ;alue.
Change from baseline in laboratory valuesI %cont.*
,rolac"in S ng[ml
Mean T&E \?.1T1.2 \;.+T1.4 1%.4T1.% 0.4T1.< \4.%T1.?
Median \0.; \2.< ;.2 1.4 \2.4
EEo!ure9adju!"ed mean T&E \*.1T1.4 \10.?T1.4 1+.*T1.4 \1.2T1.? \%.?T1.; B0.001
7lectrocardiographic findings!!
Mean 6T&E7 change in correc"ed GT in"er(al from )a!e9 1.2T1.* %.;T1.; 0.2T1.* 1.4T2.0 1.+T2.2 0.2%
line "o la!" o)!er(a"ion S m!ec
,rolonged correc"ed GT in"er(al S no.["o"al no. 6U7 0[2+1 ?[214 6+7 <[21* 6+7 2[1<2 617 2[14* 617 0.0+
&e? cataracts 4 no.Gtotal no. %5*.. +[2<2 617 1[2%* 6B17 2[2?0 617 1[210 6B17 0[142 0.*1
8edications added 4 no. %5*<<
.i"hium 1 6B17 4 617 2 6B17 + 617 1 6B17 0.42
'n"icon(ul!an"! 10 6+7 11 6+7 1+ 647 ; 6+7 * 647 0.?+
'n"idere!!an"!WW 40 6127 2* 6*7 %4 61?7 2* 6117 2? 6147 0.0+
/yno"ic!, !eda"i(e!XX 22 6<7 14 647 +2 6;7 2+ 6;7 1< 6;7 0.0+
'nEioly"ic! +1 6;7 4? 6147 ++ 6107 +* 61%7 2< 61%7 B0.001
'n"icholinergic agen"! 2% 6<7 11 6+7 +2 6;7 2? 6107 14 6*7 0.01
2ral gluco!e9lowering drug!, in!ulin 12 647 < 627 * 627 % 627 4 627 0.;%
#hole!"a"in drug! 1% 647 14 647 11 6+7 < 6+7 2 617 0.2*
8 ,a"ien"! wi"h "ardi(e dy!1ine!ia were eEcluded from "he erhena-ine grou.
Z , (alue!, re!en"ed for de!cri"i(e uro!e!, are from a "e!" wi"h 4 df comaring all "rea"men" grou!. , (alue! for rea!on! of di!con"inua9 "ion are from a chi9!>uare "e!". , (alue! for ercen"age!
are from a ,oi!!on regre!!ion accoun"ing for differen"ial eEo!ure "ime! and adju!"9 ing for whe"her "he a"ien" had had an eEacer)a"ion in "he receding "hree mon"h!. , (alue! for a rolonged
correc"ed GT in"er(al and new ca"arac"! are from Fi!herK! eEac" "e!". , (alue! for la)ora"ory (alue! are )a!ed on a ran1ed analy!i! of co(ariance wi"h adju!"men" for whe"her "he a"ien" had had an
eEacer)a"ion in "he receding "hree mon"h! and "he dura"ion of eEo!ure "o "he !"udy drug during ha!e 1. , (alue! for "he change in weigh" and "he correc"ed GT in"er(al are )a!ed on an analy!i!
of co(ariance wi"h adju!"men" for whe"her "he a"ien" had had an eEacer)a"ion in "he receding "hree mon"h! and "he dura"ion of eEo!ure "o !"udy drug during ha!e 1.
V ,ercen"age! are )a!ed on "he num)er of female a"ien"!A ;2 in "he olan-aine grou, *2 in "he >ue"iaine grou, ** in "he ri!eridone grou,
?2 in "he erhena-ine grou, and %? in "he -ira!idone grou.
W &core! of 2 or more on "he ')normal 5n(olun"ary Mo(emen" &cale 6'5M&7 glo)al !e(eri"y !core indica"e a" lea!" mild !e(eri"y of a)normal mo(emen"!. ,ercen"age! are )a!ed on "he num)er of
a"ien"! wi"hou" "ardi(e dy!1ine!ia who had an '5M& !core of le!! "han 2 a" )a!eline and a" lea!" one o!"9)a!eline mea!uremen". &core! of + or more for "he glo)al clinical a!!e!!men" of "he
4arne! '1a"hi!ia 0a"ing &cale in9 dica"e a" lea!" modera"e !e(eri"y of a1a"hi!ia. ,ercen"age! are )a!ed on "he num)er of a"ien"! who had a 4arne! !core of le!! "han + a" )a!eline and a" lea!" one o!"9
)a!eline mea!uremen". '(erage !core! of 1 or more for "he &im!on P 'ngu! EE"rayramidal &ign! &cale indica"e a" lea!" mild !e(eri"y of eE"rayramidal !ign!. ,ercen"age! are )a!ed on "he
num)er of a"ien"! who had an a(erage !core for "he &im!on P 'ngu! EE"rayramidal &ign! &cale of le!! "han 1 a" )a!eline and a" lea!" one o!"9)a!eline mea!uremen".
X ,ercen"age! for weigh" gain are )a!ed on "he num)er of a"ien"! wi"h a )a!eline and a" lea!" one o!"9)a!eline mea!uremen". To con(er" (al9 ue! for weigh" "o 1ilogram!, di(ide )y 2.2. The range for
weigh" change i! "he %"h "o ;%"h ercen"ile, which eEclude! eE"reme ou"lier!.
Y ,a"ien"! were in!"ruc"ed "o fa!"D nonfa!"ing re!ul"! were no" eEcluded. #hange wa! de"ermined a! "he difference )e"ween "he )a!eline (alue and "he a(erage of "he "wo highe!" o!"9)a!eline (alue!.
The eEo!ure9adju!"ed mean i! "he lea!"9!>uare! mean from an analy!i! of co9 (ariance adju!"ing for whe"her "he a"ien" had had an eEacer)a"ion in "he receding "hree mon"h! and for dura"ion
of eEo!ure "o !"udy drug during ha!e 1. &ince "he mea!uremen" of glyco!yla"ed hemoglo)in wa! added "o "he ro"ocol a! ar" of a ro"ocol amendmen", "he num)er! of a"ien"! are !maller for
"hi! "e!"A 1%1 in "he olan-aine grou, 1+< in "he >ue"iaine grou, 1+; in "he ri!eridone grou, 10< in "he erhena-ine grou, and *; in "he -ira!idone grou. The analy!i! of all o"her
la)ora"ory (aria)le! included 2*? a"ien"! in "he olan9 -aine grou, 2?* in "he >ue"iaine grou, 2?2 in "he ri!eridone grou, 212 in "he erhena-ine grou, and 14+ in "he -ira!idone grou. To
con(er" (alue! for )lood gluco!e "o millimole! er li"er, mul"ily )y 0.0%%%1. To con(er" (alue! for chole!"erol "o millimole! er li"er, mul9 "ily )y 0.02%*?. To con(er" (alue! for "riglyceride! "o
millimole! er li"er, mul"ily )y 0.0112;.
88 ,ercen"age! are )a!ed on "he num)er of a"ien"! who had a normal correc"ed GT in"er(al a" )a!eline 64%0 m!ec or le!! for men and 4<0 m!ec or le!! for women7 and a" lea!" one o!"9)a!eline
mea!uremen".
ZZ ,ercen"age! are )a!ed on "he num)er of a"ien"! wi"h a o!"9)a!eline a!!e!!men".
VV ,ercen"age! are )a!ed on "he num)er of a"ien"! wi"h da"a a(aila)leA +++ in "he olan-aine grou, +++ in "he >ue"iaine grou, +40 in "he ri!9 eridone grou, 2%; in "he erhena-ine grou, and 1*4
in "he -ira!idone grou.
WW Tra-odone wa! eEcluded.
XXTra-odone wa! included.
n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
1221
The new england journal of medicine
gain and increa!e! in glyco!yla"ed hemoglo)in, chole!"erol, and
"riglyceride!, change! "ha" may ha(e !eriou! imlica"ion! wi"h re!ec" "o
medical comor9 )idi"y !uch a! "he de(elomen" of "he me"a)olic !yndrome.
/ow clinician!, a"ien"!, familie!, and olicyma1er! e(alua"e "he "rade9off!
)e"ween effi9 cacy and !ide effec"!, a! well a! drug rice!, will de9 "ermine
fu"ure a""ern! of u!e.
&uor"ed )y a gran" 6N01 M/;00017 from "he N5M/ and )y "he Founda"ion of /oe of 0aleigh,
N.#. '!"ra@eneca ,harmaceu"ical!, 4ri!"ol9Myer! &>ui)), Fore!" ,harmaceu"ical!, Jan!!en ,harmaceu9
"ica, Eli .illy, 2"!u1a ,harmaceu"ical, ,fi-er, @eni"h Ooldline ,har9 maceu"ical!, &chering9,lough, and
No(ar"i! ro(ided medica"ion! for "he !"udie!.
Dr. .ie)erman reor"! ha(ing recei(ed re!earch funding from '!"ra@eneca ,harmaceu"ical!,
4ri!"ol9Myer! &>ui)), OlaEo&mi"h9 3line, Jan!!en ,harmaceu"ica, and ,fi-er and con!ul"ing and educa9
"ional fee! from '!"ra@eneca ,harmaceu"ical!, 4ri!"ol9Myer! &>ui)), Eli .illy, Fore!" ,harmaceu"ical!,
OlaEo&mi"h3line, Jan!!en ,harma9 ceu"ica, No(ar"i!, ,fi-er, and &ol(ay. Dr. &"rou reor"! ha(ing
re9 cei(ed re!earch funding from Eli .illy and con!ul"ing fee! from Jan!9 !en ,harmaceu"ica,
OlaEo&mi"h3line, and 4ri!"ol9Myer! &>ui)). Dr. McE(oy reor"! ha(ing recei(ed re!earch funding
from '!"ra9 @eneca, Fore!" 0e!earch 5n!"i"u"e, Eli .illy, Jan!!en ,harmaceu"ica, and ,fi-erD con!ul"ing
or ad(i!ory9)oard fee! from ,fi-er and 4ri!"ol9 Myer! &>ui))D and lec"ure fee! from Jan!!en
,harmaceu"ica and 4ri!"ol9Myer! &>ui)). Dr. &war"- reor"! ha(ing recei(ed re!earch funding from
Eli .illy and con!ul"ing and educa"ional fee! from
'!"ra@eneca ,harmaceu"ical!, 4ri!"ol9Myer! &>ui)), Eli .illy, and ,fi-er. Dr. 0o!enhec1
reor"! ha(ing recei(ed re!earch funding from '!"ra@eneca ,harmaceu"ical!, 4ri!"ol9Myer!
&>ui)), and Eli .illy and con!ul"ing fee! from 4ri!"ol9Myer! &>ui)), Eli .illy, and Jan!9 !en
,harmaceu"ica. Dr. ,er1in! reor"! ha(ing recei(ed re!earch funding from '!"ra@eneca
,harmaceu"ical!, 4ri!"ol9Myer! &>ui)), 2"!u1a ,harmaceu"ical, Eli .illy, Jan!!en
,harmaceu"ica, and ,fi-er and con!ul"ing and educa"ional fee! from '!"ra@eneca ,harmaceu9
"ical!, 4ri!"ol9Myer! &>ui)), Eli .illy, Jan!!en ,harmaceu"ical!, and ,fi-er. Dr. 3eefe reor"!
ha(ing recei(ed re!earch funding from '!"ra9 @eneca, Eli .illy, and Jan!!en ,harmaceu"icaD
con!ul"ing or ad(i!ory9 )oard fee! from Fore!" ,harmaceu"ical!, Eli .illy, Jan!!en ,harma9
ceu"ica, ,fi-er, and 4ri!"ol9Myer! &>ui))D and lec"ure fee! from Eli .illy and Jan!!en
,harmaceu"ica. Dr. &onia Da(i! i! an emloyee of Guin"ile!. Dr. #larence Da(i! reor"!
ha(ing recei(ed con!ul"ing fee! from Eli .illy and Guin"ile!. Dr. .e)owi"- i! a former
emloyee and M!. &e(ere and Dr. /!iao are curren" emloyee! of "he N5M/.
:e are inde)"ed "o "he 14;+ ar"ician"! in "he #'T5E !"udyD "o "he la"e Mahmoud '.
,ar!a, M.D., of "he Dear"men" of ,!ychia"ry, #a!e :e!"ern 0e!er(e =ni(er!i"y, #le(elandD "o
Oray!on &. Nor>ui!", M.D., M.&.,./., re(iou!ly direc"or of "he Di(i!ion of &er(ice! and
5n"er(en"ion 0e!earch, N5M/, and curren"ly chairman of "he De9 ar"men" of ,!ychia"ry and
/uman 4eha(ior, =ni(er!i"y of Mi!!i!9 !ii Medical #en"er, Jac1!onD "o 5ngrid 0oja!9Eloi,
4.&., rojec" manager of "he #'T5E !"udy, and Tiffany /arri!, !"aff a!!i!"an", De9 ar"men" of
,!ychia"ry, &chool of Medicine, =ni(er!i"y of Nor"h #arolina a" #hael /illD "o 'lli!on
'ndor!, ,h.D., direc"or of Oran"! De(elomen" a" "he 0e!earch Founda"ion for Men"al
/ygiene, New For1 &"a"e ,!ychia"ric 5n!"i"u"eD and "o "he Guin"ile! #'T5E rojec" "eam.
appendi F
The #'T5E &"udy 5n(e!"iga"or! Orou include! "he followingA .. 'dler, #linical 5n!igh"!, Olen 4urnie, Md.D M. 4ari, &ynergy #linical 0e9 !earch, #hula Li!"a, #alif.D 5. 4el-, Tri9#oun"y[Men"al /eal"h
and Men"al 0e"arda"ion &er(ice!, #onroe, TeE.D 0. 4land, &ou"hern 5llinoi! =ni(er!i"y &chool of Medicine, &ringfieldD T. 4locher, Men"al /eal"h and Men"al 0e"arda"ion 'u"hori"y of /arri! #oun"y,
/ou!"onD 4. 4ol9 yard, #oE Nor"h /o!i"al, &ringfield, Mo.D '. 4uffen!"ein, GueenK! Medical #en"er, /onoluluD J. 4urru!!, 4aylor #ollege of Medicine, /ou!"onD M. 4yerly, =ni(er!i"y of TeEa!
&ou"hwe!"ern Medical #en"er a" Dalla!, Dalla!D J. #ani(e, 'l)u>uer>ue Le"eran! 'ffair! Medical #en"er, 'l)u>uer>ue, N.M.D &. #aroff, 4eha(ioral /eal"h &er(ice, ,hiladelhiaD #. #a!a", 4eha(ioral
/eal"h #en"er, #harlo""e, N.#.D E. #ha(e-90ice, El ,a!o #ommuni"y Men"al /eal"h and Men"al 0e"arda"ion #en"er, El ,a!o, TeE.D J. #!ernan!1y, :a!hing"on =ni(er!i"y &chool of Medicine, &". .oui!D
,. Delgado, =ni(er!i"y /o!i"al! of #le(eland, #le(elandD 0. Douyon, Le"eran! 'ffair! Medical #en"er, MiamiD #. DK&ou-a, #onnec"icu" Men"al /eal"h #en"er, New /a(enD 5. Olic1, &"anford =ni(er!i"y
&chool of Medicine, &"anford, #alif.D D. Ooff, Ma!9 !achu!e""! Oeneral /o!i"al, 4o!"onD &. Ora"-, Ea!"ern ,enn!yl(ania ,!ychia"ric 5n!"i"u"e, ,hiladelhiaD O.T. Oro!!)erg, &ain" .oui! =ni(er9 !i"y
&chool of MedicineP:ohl 5n!"i"u"e, &". .oui!D M. /ale, New 4ri"ain Oeneral /o!i"al, New 4ri"ain, #onn.D M. /amner, Medical =ni(er9 !i"y of &ou"h #arolina and Le"eran! 'ffair! Medical #en"er,
#harle!"onD 0. Jaffe, 4elmon" #en"er for #omrehen!i(e Trea"men", ,hiladelhiaD D. Je!"e, =ni(er!i"y of #alifornia, &an Diego, Le"eran! 'ffair! Medical #en"er, &an DiegoD '. 3a)linger, .oui!iana
&"a"e =ni9 (er!i"y /eal"h &cience! #en"er, &hre(eor"D '. 3han, ,!ychia"ric 0e!earch 5n!"i"u"e, :ichi"a, 3an!.D &. .am)er"i, =ni(er!i"y of 0oche!"er Medical #en"er, 0oche!"er, N.F.D M.T. .e(y, &"a"en
5!land =ni(er!i"y /o!i"al, &"a"en 5!land, N.F.D J.'. .ie)erman, =ni(er!i"y of Nor"h #aro9 lina &chool of Medicine, #hael /illD O. Maguire, =ni(er!i"y of #alifornia 5r(ine, 2rangeD T. Man!chrec1,
#orrigan Men"al /eal"h #en"er, Fall 0i(er, Ma!!.D J. McE(oy, Du1e =ni(er!i"y Medical #en"er, Durham, N.#.D M. McOee, 'alachian ,!ychia"ric /eal"hcare &y!"em, '"h9 en!, 2hioD /. Mel"-er,
Lander)il" =ni(er!i"y Medical #en"er, Na!h(illeD '. Miller, =ni(er!i"y of TeEa! /eal"h &cience #en"er a" &an 'n"onio, &an 'n"onioD D.D. Miller, =ni(er!i"y of 5owa, 5owa #i"yD /. Na!rallah, =ni(er!i"y of
#incinna"i Medical #en"er, #incinna"iD #. Nemeroff, Em9 ory =ni(er!i"y &chool of Medicine, '"lan"aD &. 2l!on, =ni(er!i"y of Minne!o"a Medical &chool, Minneaoli!D O.F. 2Een1rug, &". Eli-a)e"hK!
Medical #en"er, 4o!"onD J. ,a"el, =ni(er!i"y of Ma!!achu!e""! /eal"h #are, :orce!"erD F. 0eimherr, =ni(er!i"y of ="ah Medical #en"er, &al" .a1e #i"yD &. 0iggio, Moun" &inai Medical #en"erP4ronE
Le"eran! 'ffair! Medical #en"er, 4ronE, N.F.D &. 0i!ch, =ni(er!i"y of #alifornia, &an Franci!co, &an Franci!coD 4. &al"-, Men"al /eal"h 'd(oca"e!, 4oca 0a"on, Fla.D T. &ima"ico, Nor"hwe!"ern
=ni(er!i"y, #hicagoD O. &im9 !on, =ni(er!i"y of &ou"hern #alifornia Medical #en"er, .o! 'ngele!D M. &mi"h, /ar)orP=#.' Medical #en"er, Torrance, #alif.D 0. &ommi, =ni(er!i"y of Mi!!ouri, 3an!a!
#i"yD 0.M. &"ein)oo1, =ni(er!i"y of Miami &chool of Medicine, MiamiD M. &"e(en!, Lalley Men"al /eal"h, &al" .a1e #i"yD '. Ta, Le"eran! 'ffair! ,uge" &ound /eal"h #are &y!"em, Tacoma, :a!h.D 0.
Torre!, =ni(er!i"y of Mi!!i!!ii, Jac1!onD ,. :eiden, &=NF Down!"a"e Medical #en"er, 4roo1lyn, N.F.D J. :ol)erg, Moun" &inai Medical #en"er, New For1.
1222 n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
effec"i(ene!! of an"i!ycho"ic drug! in chronic !chi-ohrenia
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n engl j med +%+D12 www.nejm.or g !e"em)er 22, 200%
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