Of-Label Use of Sodium Valproate for Schizophrenia

Author: Horowitz, Einav; Bergman, Lisa Carroll; Ashkenazy, Charna; Moscona-Hurvitz, Irit;
rinval!-"ogel, Haya; Magnezi, #acheli
Abstract: Backgroun!
$%-la&el use o' a !rug not accor!ing to its regulatory la&eling has &ecome common in me!icine,
es(ecially in the )el! o' (sychiatry* Moo! sta&ilizers are inten!e! to &e use! to attenuate moo!
+uctuations in &i(olar !isor!er, &ut their use has s(rea! to (atients with schizo(hrenia, as it
(rovi!es greater control o' im(ulsivity an! aggressiveness* ,o!ium val(roate is one o' the most
're-uently use! moo! sta&ilizers in (sychiatry* .his stu!y !etermine! the (revalence o' o%-la&el
use o' so!ium val(roate 'or schizo(hrenia an! schizoa%ective !isor!er in A&ar&anel /sychiatric
Hos(ital an! the !emogra(hic an! clinical characteristics associate! with its use*
Metho!s
#etros(ective stu!y o' (atients hos(italize! in 0122-0120 with a !iagnosis o' schizo(hrenia or
schizoa%ective !isor!er in one o' three general (sychiatric war!s*
#esults
3al(roate use was signi)cantly lower in the geriatric grou( 422*56 vs* 01*26, chi s-uare 7 8*9, (
7 *1:;, in (atients with schizo(hrenia 428*26 vs* schizoa%ective !isor!er 4:<*06;, chi s-uare 7
0=, (>*112; an! in (atients receiving &oth aty(ical an! ty(ical anti(sychotics 40:*:6 vs* 25*86, (
7 *18;* In multivariate logistic regression analysis, !iagnosis an! the com&ination o' aty(ical an!
ty(ical anti(sychotics (re!icte! the use o' so!ium val(roate* .he num&er o' other me!ications
(rescri&e! !i! not (re!ict so!ium val(roate use*
Conclusions
$%-la&el use o' so!ium val(roate in (sychiatric (atients with schizo(hrenia or schizoa%ective
!isor!er is e?tensive, es(ecially in younger (atients an! those with schizoa%ective !isor!er* More
research is nee!e! to !etermine whether it is &eing (rescri&e! a((ro(riately*
Full text: A&stract
Backgroun!
$%-la&el use o' a !rug not accor!ing to its regulatory la&eling has &ecome common in me!icine,
es(ecially in the )el! o' (sychiatry* Moo! sta&ilizers are inten!e! to &e use! to attenuate moo!
+uctuations in &i(olar !isor!er, &ut their use has s(rea! to (atients with schizo(hrenia, as it
(rovi!es greater control o' im(ulsivity an! aggressiveness* ,o!ium val(roate is one o' the most
're-uently use! moo! sta&ilizers in (sychiatry* .his stu!y !etermine! the (revalence o' o%-la&el
use o' so!ium val(roate 'or schizo(hrenia an! schizoa%ective !isor!er in A&ar&anel /sychiatric
Hos(ital an! the !emogra(hic an! clinical characteristics associate! with its use*
Metho!s
#etros(ective stu!y o' (atients hos(italize! in 0122-0120 with a !iagnosis o' schizo(hrenia or
schizoa%ective !isor!er in one o' three general (sychiatric war!s*
#esults
3al(roate use was signi)cantly lower in the geriatric grou( 422*56 vs* 01*26, chi s-uare 7 8*9, (
19 @uly 0128 /age 2 o' 22 /roAuest
7 *1:;, in (atients with schizo(hrenia 428*26 vs* schizoa%ective !isor!er 4:<*06;, chi s-uare 7
0=, (>*112; an! in (atients receiving &oth aty(ical an! ty(ical anti(sychotics 40:*:6 vs* 25*86, (
7 *18;* In multivariate logistic regression analysis, !iagnosis an! the com&ination o' aty(ical an!
ty(ical anti(sychotics (re!icte! the use o' so!ium val(roate* .he num&er o' other me!ications
(rescri&e! !i! not (re!ict so!ium val(roate use*
Conclusions
$%-la&el use o' so!ium val(roate in (sychiatric (atients with schizo(hrenia or schizoa%ective
!isor!er is e?tensive, es(ecially in younger (atients an! those with schizoa%ective !isor!er* More
research is nee!e! to !etermine whether it is &eing (rescri&e! a((ro(riately*
CitationB Horowitz E, Bergman LC, Ashkenazy C, Moscona-Hurvitz I, rinval!-"ogel H, et al* 40128;
$%-La&el Cse o' ,o!ium 3al(roate 'or ,chizo(hrenia* /Lo, $DE =4:;B e=0<9:*
!oiB21*2:92EFournal*(one*11=0<9:
E!itorB @ames G* Clellan!, .he Dathan Hline Institute, Cnite! ,tates o' America
#eceive!B ,e(tem&er =, 012:; Acce(te!B "e&ruary 08, 0128; /u&lishe!B March 08, 0128
Co(yrightB 0128 Horowitz et al* .his is an o(en-access article !istri&ute! un!er the terms o' the
Creative Commons Attri&ution License, which (ermits unrestricte! use, !istri&ution, an!
re(ro!uction in any me!ium, (rovi!e! the original author an! source are cre!ite!*
"un!ingB .he authors have no su((ort or 'un!ing to re(ort*
Com(eting interestsB $ne o' the authors is a lo&al Clinical ,u((ly Chain /lanner 'or lo&al
Clinical $(erations grou( at .eva /harmaceutical In!ustries whose Fo& is to (lan an! e?ecute the
su((ly chain 'or .evaIs clinical stu!ies worl!wi!e, make sure .eva (ro!uces the right amounts o'
(ro!uct nee!e! to meet the !eman! o' the stu!y, an! then arrange 'or those (ro!ucts to &e
shi((e! to hos(itals aroun! the worl! where .evaIs stu!y is con!ucte!* .he sco(e o' the Fo&
inclu!es !rugs that are in !evelo(ment only; it !oes not have anything to !o with any markete!
(ro!ucts* .his !oes not alter the authorsI a!herence to all the /L$, $DE (olicies on sharing !ata
an! materials*
Intro!uction
$%-la&el use 4$LC; - the use o' a !rug or a !evice 'or a (ur(ose or in a manner outsi!e its
regulatory la&eling - has &ecome a common (ractice in many )el!s o' me!icine J2K* #a!ley et al*
'oun! that 026 o' (rescri(tions given to (atients in general oLce (ractices were 'or o%-la&el
in!ications J0K* ,enior clinicians an! regulators 'rom a num&er o' Euro(ean countries an! Dorth
America regar! o%-la&el (rescri&ing as a necessary (art o' the art o' me!icine J:K*
$LC is (articularly common in (sychiatry* .he lack o' clarity regar!ing the (hysiological &asis 'or
(sychiatric !isor!ers, the relative ine%ectiveness 4an! sometimes trou&lesome si!e-e%ects; o'
various !rugs an! the sym(toms share! &y many o' the !isor!ers, have le! (hysicians to use
!rugs a((rove! 'or one !isor!er 'or one 'or which it is not a((rove! J8K* Leslie et al* re(orte! that
more than hal' o' (sychiatrists surveye! routinely (rescri&e! (sychotro(ic me!ications o%-la&el
J<K* .he (henomenon o' o%-la&el (rescri&ing is so common that in some instances, (sychiatrists
are not aware that they are (rescri&ing o%-la&el J5K*
Anti(sychotics 4ty(ical an! aty(ical; are still the cornerstone o' schizo(hrenia treatment* Many
in!ivi!uals with schizo(hrenia re-uire a com&ination o' !rugs, inclu!ing !i%erent classes o' !rugs,
19 @uly 0128 /age 0 o' 22 /roAuest
such as anti!e(ressants, an?iolytics, moo! sta&ilizers an! various other me!ications to treat the
si!e-e%ects o' the neurole(tic treatments* /oly(harmacy is common* $ne-)'th to one-thir! o'
in!ivi!uals with schizo(hrenia !oes not res(on! to anti(sychotics J9K*
Moo! sta&ilizers are thus name! &ecause they attenuate the moo! +uctuations o' (atients with
&i(olar !isor!er, &ut their usage has s(rea! to other (sychiatric con!itions* Cnlike the
com&ination o' aty(ical anti(sychotics an! moo! sta&ilizers in &i(olar !isor!er, the use o' so!ium
val(roate in (atients with schizo(hrenia has limite! em(irical evi!ence JMK, J=K* It there'ore
remains an o%-la&el in!ication* Ges(ite that, the use o' moo! sta&ilizers as augmentation thera(y
'or schizo(hrenic (atients has &ecome wi!es(rea!* .he utilization rates o' moo! sta&ilizers in
(atients with schizo(hrenia range 'rom 2<6 to almost <16 J2K, J21K-J28K*
,o!ium val(roate was originally !evelo(e! as an anticonvulsant an! was later a((rove! 'or manic
e(iso!es associate! with &i(olar !isor!er J2<K, J25K* In the (ast !eca!e, it &ecame the most
're-uently (rescri&e! moo! sta&ilizer 'or (atients with schizo(hrenia, with lithium lagging 'ar
&ehin! J2K, J21K, J22K, J28K*
.he goal o' this stu!y was to !etermine the (revalence o' o%-la&el so!ium val(roate (rescri(tion
'or schizo(hrenia an! schizoa%ective !isor!er in a maFor (sychiatric hos(ital in Israel an! to
!etermine the !emogra(hic an! clinical characteristics associate! with its use*
Metho!s
.his retros(ective stu!y was con!ucte! at the A&ar&anel Mental Health Center, the largest
(sychiatric 'acility in Israel, using a com(uterize! !ata&ase* .his :11-&e! aca!emic hos(ital
covers a (o(ulation o' a((ro?imately one million* It (rovi!es treatment 'or in!ivi!uals with
(ersonality !isor!ers, as well as neurotic, (sychotic an! organic con!itions* In a!!ition, the center
o%ers out-(atient services, (sychiatric reha&ilitation an! long-term (sychiatric !ay-care* /atients
range in age 'rom youth to the el!erly*
/atients with a !iagnosis o' schizo(hrenia 4ICG co!es "*01-"*01*=; or schizoa%ective !isor!er 4ICG
co!e "*0<; hos(italize! 'rom 0122 through 0120 in a general war! 'or men or women or in a
geriatric war! were inclu!e! in this stu!y* I' a (atient ha! &oth !iagnoses, the most recent one
was use!* /atients were e?clu!e! i' they ha! a concomitant !iagnosis o' e(ile(sy or &i(olar
!isor!er, &oth la&ele! in!ications 'or so!ium val(roate*
Gata e?tracte! 'rom the electronic me!ical recor! system inclu!e! age, gen!er, hos(ital
a!mission an! !ischarge !ates, !iagnosis an! treatment* I' a (atient was hos(italize! more than
once within the stu!y (erio!, !ata 'rom the most recent hos(italization were use!* Me!ications
use! &y the (atients were grou(e! into the 'ollowing categoriesB ty(ical 4)rst generation;
anti(sychotics, aty(ical 4secon! generation; anti(sychotics, anti!e(ressants, an?iolytics, moo!
sta&ilizers 4other than so!ium val(roate; an! so!ium val(roate*
Ethics statement
.he stu!y was a((rove! &y the A&ar&anel Hos(ital Ethics #eview Boar!* .he Ethics #eview Boar!
grante! a((roval to review the (atient recor!s an! e?tract the necessary !ata* .he Ethics #eview
Boar! waive! the nee! to o&tain in!ivi!ual in'orme! consent &ecause the !ata were analyze!
anonymously*
Measures
.he num&er o' !rug ty(es (rescri&e! 'or a (atient 4other than so!ium val(roate; was calculate!
19 @uly 0128 /age : o' 22 /roAuest
as a count o' the )ve categories inclu!e! in the stu!y 4ty(ical anti(sychotics, aty(ical
anti(sychotics, anti!e(ressants, an?iolytics an! moo! sta&ilizers;, yiel!ing a scale ranging 'rom 1
to <* Anti(sychotic (oly(harmacy 4A//; was !e)ne! as a com&ination o' ty(ical with aty(ical
anti(sychotics* "or logistic regression, !ichotomous varia&les were use! to analyze the e%ect o'
gen!er, war! an! !iagnosis*
,tatistical Analysis
All statistical analyses were (er'orme! using the ,/,, statistical so'tware, version 01*1* .he N0
test 'or in!e(en!ence was carrie! out to e?amine the !e(en!ency &etween the !iagnosis an! the
war! to the use o' so!ium val(roate*
Logistic regression was use! to e?amine gen!er, !iagnosis, war! an! num&er o' !rug ty(es an!
A// as (otential (re!ictors o' the use o' so!ium val(roate* $!!s ratios with =<6 con)!ence
intervals were calculate! 'or each in!e(en!ent varia&le*
#esults
Among a((ro?imately 2,:11 hos(italizations, 518 in!ivi!uals matche! the inclusion an! e?clusion
criteria, 0<: in the menIs war!, 0:1 in the womenIs war! an! 202 in the geriatric war!* .he
average age o' the (atients was 8<*= 4,G 28*9; years* .he age range in the menIs war! was 2M to
5< years, in the womenIs war!, 2= to 58 years an! in the geriatric war!, 'rom 51 to M< years*
/atient characteristics are (resente! in .a&le 2* A total o' 8M0 49=*M6; were !iagnose! with
schizo(hrenia*
.a&le 2* /atient !emogra(hics an! me!ications &y war!*
.he most commonly (rescri&e! me!ications were anti(sychotics; over =96 o' (atients receive!
at least one* eriatric (atients ten!e! to receive aty(ical rather than ty(ical anti(sychotics
4M<*=6 vs* 09*:6 o' (atients;, while use o' ty(ical anti(sychotics was slightly more 're-uent in
the general war!s 45=*06 ty(ical vs* 51*86 aty(ical; .a&le 2;*
.he anti(sychotics (rescri&e! an! 're-uencies are shown in .a&le 0* $' the aty(ical
anti(sychotics, clotia(ine an! olanza(ine were most (o(ular* .here were !i%erences in choice o'
ty(ical anti(sychotics on the menIs an! womenIs war!s* Ouclo(enthi?ol was most common on the
menIs war! an! halo(eri!ol in the womenIs war!* Although ty(ical anti(sychotics were
in're-uently use! on the geriatrics war!, zuclo(enthi?ol an! halo(eri!ol were 'avore!*
.a&le 0* .y(es o' anti(sychotics &y war!*
$n average, (atients receive! 0*8 ty(es o' !rugs 4me!ian 0; other than val(roate* /atients in the
general male an! 'emale war!s receive! signi)cantly more ty(es o' !rugs 40*<P1*= vs* 0*:P1*M,
res(ectively; ( 7 1*129; than the geriatric (atients 42*8P1*5; (>1*112;* .here was no !i%erence
&etween men an! women in the num&er o' !rug ty(es receive!* Qhereas :2*56 o' (atients 4D 7
2=2; were (rescri&e! only ty(ical anti(sychotic me!ications, :5*86 4D 7 001; were (rescri&e!
only aty(ical anti(sychotic me!ications an! 0=*26 receive! &oth ty(ical an! aty(ical
anti(sychotic me!ications 4A//;* $' those (atients with A//, zuclo(enthi?ol 4:5*=6, D 7 5<;,
halo(eri!ol 4:8*26, D 7 51; an! +u(henazine 402*56, D 7 :M; were the most commonly
(rescri&e! ty(ical anti(sychotics* $' those receiving A//, the most common aty(ical
anti(sychotics (rescri&e! were clotia(ine 481*=6, D 7 90;, -uetie(ine 42:*56, D 7 08; an!
amisul(ri!e 4M*16, D 7 28;* At least one moo! sta&ilizer, inclu!ing so!ium val(roate was
(rescri&e! 'or 2<9 4056; o' the in!ivi!uals inclu!e! in the stu!y*
19 @uly 0128 /age 8 o' 22 /roAuest
$verall, 222 (atients 42M*86; receive! so!ium val(roate* "re-uencies an! (ercentages o' so!ium
val(roate use &y war! an! !iagnosis are shown in .a&le 2* .here were no gen!er !i%erences
within the menIs an! womenIs war!s &etween (atients who receive! so!ium val(roate an! those
who !i! not 4N042; 7 1*52M, (R1*1<;* ,o!ium val(roate use was signi'icantly more common in
(atients in the general war!s 401*26; than among the geriatric (atients 422*56; (>1*1<; an! in
(atients with schizoa%ective !isor!er 4:<*06; vs* schizo(hrenia 428*26; (>1*112; 4.a&le :;*
.a&le :* "re-uency an! (ercentage o' so!ium val(roate use &y war! an! !iagnosis*
,o!ium val(roate use was similar among (atients who receive! anti(sychotics, anti!e(ressants
an! an?iolytics, ranging &etween 286 an! 00*06 4.a&le 8;* It was also more commonly (rescri&e!
'or (atients receiving A//* ,o!ium val(roate was com&ine! with another moo! sta&ilizer in seven
(atients*
.a&le 8* "re-uency an! (ercentage o' so!ium val(roate use &y num&er an! ty(e o' !rugs*
In the logistic regressions, the o!!s ratios 4$#; !escri&ing the relative risk o' using so!ium
val(roate with gen!er, !iagnosis an! war! were all greater than one 4.a&les < an! 5;* Giagnosis
was associate! with the highest risk estimate* /atients with a !iagnosis o' schizoa%ective !isor!er
were :*9 times more likely to receive so!ium val(roate than those !iagnose! with schizo(hrenia*
en!er was not a signi)cant (re!ictor o' so!ium val(roate use* .he !i%erence &etween the
general an! geriatric war!s was not signi)cant* .he num&er o' !rug grou(s was not signi)cant in
(re!icting the use o' so!ium val(roate 4$# 2*28, =<6 CIB 1*=<-2*:M; / 7 1*2<2; 4.a&le <;*
However, in the logistic regression 4.a&le 5; inclu!ing gen!er, !iagnosis, war! an! A//, the use o'
A// was signi)cant 4$# 7 2*5:; =<6 CIB 2*1:-0*52; / 7 *18;*
.a&le <* Logistic regression (re!icting the use o' so!ium val(roate &y gen!er, war!, !iagnosis an!
num&er o' !rugs*
.a&le 5* Logistic regression (re!icting the use o' so!ium val(roate &y gen!er, !iagnosis, war! an!
num&er o' anti(sychotics*
Giscussion
.his stu!y assesse! the e?tent o' o%-la&el use o' so!ium val(roate an! A// in several war!s in a
maFor (sychiatric 'acility in Israel* .he rates o' moo! sta&ilizers an! so!ium val(roate use were
very similar to those re(orte! in Asia 4086 'or moo! sta&ilizers an! 25*96 'or so!ium val(roate;,
&ut lower than those re(orte! in the C,, where a((ro?imately hal' o' schizo(hrenic (atients
receive! moo! sta&ilizers an! a&out a thir! receive! so!ium val(roate J2K, J=K, J21K, J28K* In the
Dew Sork ,tate hos(ital system, in 2==5, a((ro?imately hal' o' all (atients !iagnose! with &i(olar
or schizoa%ective !isor!er an! 0M6 o' all (atients !iagnose! with schizo(hrenia, were (rescri&e!
val(roate* "or (atients with schizo(hrenia, that num&er increase! to :<6 &y 0112 J21K, J22K* In a
cross-sectional survey o' in-(atients 2M to 5< years o' age 'rom the Cnite! Hing!om, 0M*<6 were
receiving an o%-la&el moo! sta&ilizer J29K* $' those (atients, 0M*06 ha! a !iagnosis o'
schizo(hrenia an! 296 ha! a !iagnosis o' schizoa%ective !isor!er* .hus, o%-la&el use o' moo!
sta&ilizers was very common in this (o(ulation o' in(atients with severe mental illness* .hese
!i%erences 'rom the current stu!y, where 286 an! :<6 o' (atients with schizo(hrenia an!
schizoa%ective !isor!er, res(ectively receive! so!ium val(roate, might &e !ue to !i%erences in
(atient (o(ulation an! case-mi?* Alternatively, it might re+ect variations in the organizational or
cultural a((roaches o' the treating (hysicians to the management o' schizo(hrenia an! to the
legitimacy o' o%-la&el use in general or o' so!ium val(roate in (articular* $' (articular im(ortance,
19 @uly 0128 /age < o' 22 /roAuest
in the Cnite! ,tates, o%-la&el use is not regulate!, leaving !ecisions in the han!s o' the treating
(hysician* In Israel, however, (hysicians must o&tain (ermission to use a !rug outsi!e its la&el
in!ication* Although the (roce!ure 'or hos(italize! (atients !oes not re-uire in!ivi!ual
authorization 'or each (atient, &ut rather grants com(rehensive a((roval 'or all (atients who
re-uire the me!ication 'or the re-ueste! in!ication, the very e?istence o' such a (rocess might
increase (hysiciansI awareness o' its o%-la&el status an! !eter use*
Cnsur(risingly, use o' so!ium val(roate was consi!era&ly more (revalent in (atients with
schizoa%ective !isor!er* ,chizoa%ective !isor!er (resents as an interme!iate 'orm o' (sychotic
!isor!er &etween schizo(hrenia an! &i(olar !isor!er, although uni(olar versions o' schizoa%ective
!isor!er have &een !escri&e! J2MK, J2=K* .here'ore, treatment 'or (atients with this !isor!er
revolves aroun! a com&ination o' anti(sychotics, 'or the (sychotic sym(toms an! either anti-
!e(ressants or moo! sta&ilizers 'or the a%ective sym(toms J01K, J02K* A%ective sym(toms are not
!ominant in (atients with schizo(hrenia an! moo! sta&ilizers are generally use! only 'or
controlling im(ulsivity or violence or as augmentation 'or (atients who are unres(onsive to the
usual treatment* ,o!ium val(roate is use! 'or in!ivi!uals with schizo(hrenia with violent
e(iso!es, &ecause it is re(orte! to !ecrease aggression J00K* It is use! in treatment o' resistant
schizo(hrenia &ecause there is a great nee! 'or a!Functs to anti(sychotic !rugs J=K* ,everal
stu!ies have re(orte! some evi!ence o' eLcacy J00K-J05K* It is un!erstoo! that ABA-ergic !rugs
such as val(roate have a (otential role in the treatment o' schizo(hrenia, as they !own-regulate
!o(amine J09K* Mesolim&ic !o(amine hy(eractivity is consi!ere! one o' the main reasons 'or the
!evelo(ment o' (ositive sym(toms in schizo(hrenia* It shoul! &e note! that !es(ite the lack o'
har! evi!ence o' e%ectiveness 'or either in!ication, moo! sta&ilizers are recommen!e! 'or
schizoa%ective !isor!er, &ut not 'or schizo(hrenia* However, it can &e !iLcult to !i%erentiate the
two !isor!ers* Even the !istinction &etween schizo(hrenia an! &i(olar !isor!er has &een
challenge! &ase! on )n!ings o' a (artially share! genetic susce(ti&ility (attern* In a!!ition,
(sychotic sym(toms are (revalent in mania an! a%ective sym(toms are common in (atients with
schizo(hrenia J0MK*
In this stu!y, the use o' so!ium val(roate was almost twice as common in (atients in the general
war!s as among the geriatric (atients* .his is similar to other re(orts, where (atients treate! with
moo! sta&ilizers an!Eor so!ium val(roate were on average younger J2K, J28K* It is (ossi&le that
younger (atients have more (ositive sym(toms an! an increase! likelihoo! o' aggressive or
im(ulsive &ehavior, re-uiring the a!!ition o' moo! sta&ilizers to their treatment* Alternatively, the
relation &etween age an! war! may not &e !irect* It is (ossi&le that the !i%erence is not relate!
to the age o' the in!ivi!ual (atients (er se, &ut rather to !i%erent management o' (sychiatric
!isor!ers in geriatric war!s* iven the (hysiological 4an! (athological; changes associate! with
aging, it is logical to avoi!, i' (ossi&le, (oly(harmacy an! !rugs with a narrow thera(eutic range
in this age grou(* Moreover, stu!ies have 'oun! an increase in a!verse events 4'alls, in'ection,
gastrointestinal !isor!ers; among (atients treate! with so!ium val(roate J0=K*
/revious stu!ies have shown a relationshi( &etween in!icators 'or !isease severity or (atient
violence an! the use o' moo! sta&ilizers* ,im et al* J28K re(orte! a correlation with aggression
an! anti(sychotic (olythera(y an! /ickar et al* J2K re(orte! a correlation with a history o' violence
an! higher /ositive an! Degative ,yn!rome ,cale general (sycho(athology scores* .his stu!y !i!
not )n! a correlation with the num&er o' non-val(roate !rug ty(es* .he use o' multi(le ty(es o'
!rugs may not &e a goo! stan!-in 'or !isease severity 4i*e* use! 'or augmentation;, &ut rather
19 @uly 0128 /age 5 o' 22 /roAuest
re+ects the !i%erent clinical sym(toms a (atient mani'ests* However, use o' A//, the com&ine!
use o' ty(ical an! aty(ical anti(sychotics, was associate! with val(roate use* Qe 'oun! a
(revalence rate o' A// o' :5*86* .his is higher than the (revalence re(orte! in Dorth America
4256;, $ceania 425*86;, an! Euro(e 40:6;, &ut com(ara&le to that o' Asia 4:06; J:1K*
.he use o' A// is generally !iscourage! an! gui!elines suggest it shoul! only &e use! as a last
resort a'ter cloza(ine 4the stan!ar! o' care 'or treatment o' re'ractory (sychotic illness; J:2K-J:5K*
.his is &ecause, in a!!ition to the lack o' evi!ence &ase, the im(lications an! conse-uences 4si!e
e%ects, !osage, interactions, etc*; are unknown* In this conte?t, it is also worth noting that
cloza(ine was in're-uently (rescri&e! 4:*:6, D 7 01;* Qe suggest that use o' A// is an in!icator
o' re'ractory (sychotic illness an! there'ore associate! with val(roate use* Alternatively, its use
may re+ect a (re!is(osition &y the (rescri&ing !octor to use non-evi!ence-&ase! treatments*
An interesting, although unrelate! )n!ing was the signi)cant !i%erence in the use o' ty(ical an!
aty(ical anti(sychotics &etween general an! geriatric (atients* Aty(ical anti(sychotics are more
e%ective in treating negative sym(toms, which are more commonly 'oun! in el!erly (atients with
schizo(hrenia J:9K* .y(ical an! aty(ical anti(sychotics also have vastly !i%erent sa'ety (ro)les*
.he most signi)cant si!e-e%ects o' ty(ical neurole(tics are neurological, while aty(ical
neurole(tics are known to cause meta&olic changes, inclu!ing o&esity, hy(erli(i!emia an!
!ia&etes* Because geriatric (atients re-uire lower !oses o' the aty(ical anti(sychotics, the si!e-
e%ects occur less 're-uently* "or the el!erly, the most 're-uently re(orte! a!verse si!e-e%ects
were e?tra(yrami!al sym(toms* In most cases, the aty(ical anti(sychotics ha! 'ewer
e?tra(yrami!al sym(toms than !i! ty(ical anti(sychotics J:MK*
.he (re(on!erance o' o%-la&el use o' so!ium val(roate 'or schizo(hrenia an! schizoa%ective
!isor!er can have signi)cant clinical an! economic e%ects* Currently, there is no ro&ust evi!ence
regar!ing the e%ectiveness o' so!ium val(roate in the stan!ar! treatment o' these !isor!ers J0=K*
.here'ore, it is (ossi&le that, 'or some o' those (atients, a!!ing it to their treatment regimen !oes
not con'er &ene)ts, &ut rather e?(oses them to (otential harm* Qhile there is evi!ence that
a!!ing so!ium val(roate can &ene)t the most severe an! unmanagea&le (atients, it is unclear
whether this reason alone can account 'or the rate o' use 'oun! in this stu!y*
A!!ing so!ium val(roate increases the costs 'or me!ications 'or schizo(hrenia, &ut to !ate there
is no evi!ence that it re!uces other e?(en!itures, such as those relate! to hos(italizations J:=K*
"urthermore, in healthcare settings such as in Israel, where healthcare (rovi!ers 4Health
Maintenance $rganizations; are in (art &u!gete! accor!ing to the e?(ecte! utilization o' me!ical
technologies, o%-la&el use a!!s a new, un(lanne!, an! there'ore un&u!gete! (o(ulation o' users*
Qhile so!ium val(roate is an ine?(ensive !rug, the (revalence o' schizo(hrenia means that its
a!!ition can have a consi!era&le im(act on a (rovi!erIs &u!get* .his may also &e true o' A//* In
a!!ition to the (aucity o' clinical evi!ence su((orting &oth (ractices, there is consi!era&le
concern an! uncertainty regar!ing (ossi&le increases in si!e e%ects, higher than necessary 4or
a((rove!; total !osage, !rug-!rug interactions, increase! mortality an! cost involve! J:1K*
Limitations
.his stu!y has several limitations* "irst, !ata was collecte! 'rom three war!s in one hos(ital, an!
there'ore the )n!ings might not &e generaliza&le, es(ecially to schizo(hrenic (atients in the
community* ,econ!ly, the !ata availa&le in the !ata&ase system use! is more a!ministrative than
clinical, which limits the a&ility to truly a((reciate an! re)ne the correlation &etween (atientsI
19 @uly 0128 /age 9 o' 22 /roAuest
clinical status an! so!ium val(roate use* .his inclu!es a lack o' me!ical history in or!er to
un!erstan! the num&er o' changes in me!ications &e'ore utilizing o%-la&el o(tions* In a!!ition,
!iagnoses were &ase! on the !iagnosis entere! &y the treating (hysician in the (atient recor!
system accor!ing to ICG !iagnostic criteria an! not on !iagnostic interviews* However, such &roa!
!eterminations may &e more use'ul 'or health (olicy an! management (ur(oses*
Conclusions
$ur !ata in!icate that 'urther stu!y is necessary to !etermine the clinical consi!erations &ehin!
the use o' so!ium val(roate in (atients with (sychotic !isor!ers in Israel* iven the limite!
eLcacy evi!ence availa&le, more research is necessary to !etermine whether it is &eing
(rescri&e! a((ro(riately 'or (atients with schizoa%ective !isor!er an! 'or those with treatment-
resistant schizo(hrenia*
Author Contri&utions
Conceive! an! !esigne! the e?(erimentsB #M EH* /er'orme! the e?(erimentsB CA H-"* Analyze!
the !ataB H-"* Contri&ute! reagentsEmaterialsEanalysis toolsB CA* Qrote the (a(erB EH #M LCB*
Gata collectionB IM-H*
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Subect: ,chizo(hrenia; Bi(olar !isor!er; /sychotro(ic !rugs; /sychiatry;
!ublication title: /Lo, $ne
Volume: =
"ssue: :
!ublication #ear: 0128
!ublication date: Mar 0128
19 @uly 0128 /age 21 o' 22 /roAuest
$ear: 0128
Section: #esearch Article
!ublisher: /u&lic Li&rary o' ,cience
!lace of publication: ,an "rancisco
%ountr# of publication: Cnite! ,tates
!ublication subect: Me!ical ,ciences, ,ciencesB Com(rehensive Qorks
Source t#pe: ,cholarly @ournals
Lan&ua&e of publication: English
'ocument t#pe: @ournal Article
19 @uly 0128 /age 22 o' 22 /roAuest