Epilepsy & Behavior 26 (2013) 440449

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Epilepsy & Behavior

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)evie&

*ntiepileptic +r"$ e,,ects on #oo+ an+ behavior% -olec"lar tar$ets

.iero .er"cca a// -arco -"la
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-ontreal 0e"rolo$ical 1nstit"te/ -c2ill 3niversity/ -ontreal/ 4C/ Cana+a ivision o, 0e"rolo$y/ *#e+eo *vo$a+ro 3niversity/ 0ovara/ 1taly

a r t i c l e

i n , o

a b s t r a c t
8ith al#ost 100 years o, clinical e9perience/ antiepileptic +r"$s (*E s) re#ain the #ainstay o, epilepsy treat#ent' :hey s"ppress epileptic sei;"res by actin$ on a variety o, #echanis#s an+ #olec"lar tar$ets involve+ in the re$"lation o, ne"ronal e9citability' :hese incl"+e inhibitory<2*B*er$ic an+ e9citatory< $l"ta#ater$ic ne"rotrans#ission/ as &ell as ion (so+i"# an+ calci"#) con+"ctance thro"$h volta$e<$ate+ channels' 5n the other han+/ accr"in$ evi+ence in+icates that these #echanis#s an+ tar$ets are also i#pli< cate+ in the re$"lation o, #oo+ an+ behavior/ &hich #ay e9plain &hy each *E is associate+ &ith speci=c psychotropic e,,ects' :hese e,,ects/ ho&ever/ cannot be e9plaine+ solely on the basis o, the >no&n #o+e o, action o, each *E / an+ other #echanis#s or tar$ets are li>ely to be i#plicate+' 1n this article/ &e revie& positive an+ ne$ative e,,ects o, *E s on #oo+ an+ behavior/ +isc"ss p"tative "n+erlyin$ #echanis#s/ an+ hi$hli$ht >no&le+$e $aps &hich sho"l+ be a++resse+ in ,"t"re st"+ies' :his article is part o, a Special 1ss"e entitle+ ?:he @"t"re o, :ranslational Epilepsy )esearchA' B 2012 Elsevier 1nc' *ll ri$hts reserve+'

*rticle history% *ccepte+ 6 Septe#ber 2012 *vailable online 23 5ctober 2012 6ey&or+s% Epilepsy *ntiepileptic +r"$s epression .sychosis 7acosa#i+e )eti$abine

1' 1ntro+"ction :he intro+"ction o, appro9i#ately 1C ne& antiepileptic +r"$s (*E s) in the past 20 years has si$ni=cantly e9pan+e+ the phar#aco< lo$ical ar#a#entari"# ,or epilepsy D1E' *ltho"$h so#e o, these a$ents o,,er appreciable a+vanta$es in ter#s o, phar#aco>inetics/ tolerability/ an+ lo&er +r"$ interaction potential/ i#prove#ents in clinical o"t< co#e have ,allen short o, e9pectations/ &ith no #ore than 1C20F o, patients &ith sei;"res re,ractory to ol+er *E s attainin$ sei;"re ,ree< +o# &itho"t "nacceptable to9icity D2E' 1n this re$ar+/ treat#ent< e#er$ent a+verse psychiatric e,,ects have a consi+erable i#pact on health< relate+ G"ality o, li,e an+ #ay a,,ect patientsH co#pliance D3E' 5n the other han+/ *E s are &i+ely "se+ in psychiatric practice ,or a broa+ spectr"# o, psychiatric +isor+ers' :he pri#ary application is in #oo+ stabili;ation D4E/ b"t interestin$ +ata are also e#er$in$ ,or an9i< ety +isor+ers DCE an+ &ith+ra&al syn+ro#es D6E' 1n patients &ith epilepsy/ it is o,ten +i,=c"lt to +eter#ine &hich psy< chopatholo$ical #ani,estations are +"e speci=cally to *E therapy an+ &hich #ay be relate+ to other ,actors a,,ectin$ the patient' 1n ,act/ psy< chiatric co#plications o,ten have a #"lti,actorial ori$in &ith *E s bein$ only one o, #any p"tative ca"ses' -oreover/ the #echanis#s o, action o, several *E s are not al&ays >no&n &ith certainty' *s &ith sev< eral other +r"$ classes/ *E s have a +iversity o, actions on biolo$ical sys< te#sI only so#e o, &hich are relate+ to the +esire+ anti<sei;"re e,,ect
Correspon+in$ a"thor at% -ontreal 0e"rolo$ical 1nstit"te/ -c2ill 3niversity/ 3J01 3niversity Street/ )oo# 029/ -ontreal/ 4"ebec/ Cana+a K3* 2B4' E<#ail a++ress% piero'per"ccaLlibero'it (.' .er"cca)' 1C2C<C0C0(P see ,ront #atter B 2012 Elsevier 1nc' *ll ri$hts reserve+' http%((+9'+oi'or$(10'1016(!'yebeh'2012'09'01J

(:able 1)' :here,ore/ the psychotropic e,,ects o, *E s in epilepsy +erive ,ro# a n"#ber o, variables relate+ to the sin$le co#po"n+ (i'e'/ #echa< nis# o, action)/ to the "n+erlyin$ ne"rolo$ical con+ition (i'e'/ ne"robiol< o$y o, sei;"re control)/ an+ to the in+ivi+"al (i'e'/ ,a#ily history or personal history o, psychiatric +isor+ers) DME' 1n this article/ &e +isc"ss the role o, #echanis#s an+ #olec"lar tar$ets o, *E s in #oo+ an+ behavior/ revie& positive an+ ne$ative psychotropic e,,ects o, each *E (in chronolo$ical or+er o, licensin$/ :able 2)/ an+ hi$hli$ht c"rrent >no&le+$e $aps &hich sho"l+ be a++resse+ in ,"t"re st"+ies' 2' -echanis#s an+ #olec"lar tar$ets o, *E s in #oo+ an+ behavior 2'1' N<a#inob"tyric aci+ (2*B*) trans#ission 5ver the past 30 years/ conver$in$ evi+ence ,ro# ani#al an+ h"#an st"+ies has s"$$este+ that 2*B*er$ic #echanis#s #ay be i#plicate+ in the pathophysiolo$y o, #oo+ +isor+ers' *lterations in plas#a/ cerebrospinal O"i+/ an+ brain 2*B* levels have been ,o"n+ in e9peri#ental ani#al #o+els an+ in+ivi+"als &ith #a!or +epres< sive +isor+ers DJE' -oo+ stressors an+ psychotropic +r"$s can a,,ect 2*B*er$ic ,"nction/ an+/ conversely/ 2*B*er$ic a$ents e9ert an e,,ect on #oo+ DJE' 2a##a<a#inob"tyric aci+er$ic +ys,"nction has also been recently reporte+ to be relevant ,or the +evelop#ent o, behavioral proble#s/ s"ch as a$$ression D9E' Ben;o+ia;epines can be consi+ere+ the prototype o, psychotropic a$ents potentiatin$ the 2*B*er$ic syste#' :heir se+ative an+ an9iolytic

.' .er"cca/ -' -"la ( Epilepsy & Behavior 26 (2013) 440Q449 :able 1 ."tative #echanis#s o, action o, antiepileptic +r"$s (*E s)' *E s Volta$e<$ate+ R 0a channel bloc>a+e Barbit"rates .henytoin Ethos"9i#i+e Ben;o+ia;epines Carba#a;epine Valproate Vi$abatrin Tonisa#i+e 7a#otri$ine @elba#ate 2abapentin :opira#ate :ia$abine 59carba;epine 7evetiraceta# Stiripentol .re$abalin )"=na#i+e 7acosa#i+e Eslicarba;epine acetate )eti$abine RR RR S RR RR RR RR RR RR RR RR Volta$e<$ate+ Ca channel bloc>a+e (channel s"btype) S S RR (:) R (7) R (:) RR (0/ ./ :) RR (0/ .(4/ )/ :) R (7) RR (0/ .(4) R (7) R (0/ .(4) R (0) RR (0/ .(4)
2R

1JC

Enhance#ent o, 2*B* trans#ission RR S RR S R RR R R R S RR RR S S RR S

1nhibition o, $l"ta#ate trans#ission (receptor s"btype) S S R (0- *) R (0- *) S RR (0- */ *-.*) RR (0- *) RR (*-.*) R (0- *) S S

5ther a #echanis#s R R S R RR R R R S R R RR R RR

@irst $eneration

Secon+ $eneration

:hir+ $eneration

0aR U so+i"#/ Ca2R U calci"#' R secon+ary actionI RR pri#ary actionI not +escribe+I S controversial' a 1ncl"+e synaptic vesicle #o+"lation/ carbonic anhy+rase inhibition/ potassi"# channel activation/ an+ chlori+e channel co#ple9 interaction'

e,,ects are &i+ely reco$ni;e+' Ko&ever/ these a$ents #ay ca"se a para+o9ical +isinhibition syn+ro#e in chil+ren/ el+erly/ an+ in+ivi+"als &ith intellect"al +isabilities/ &hich is characteri;e+ by a$itation/ a$$res< siveness/ irritability/ an+ hyperactivity D10E' 1n a++ition/ the abr"pt +is< contin"ation o, ben;o+ia;epines can be acco#panie+ by severe sei;"re e9acerbation an+ chan$es in #ental stat"s/ incl"+in$ an9iety/ a$itation/ con,"sion/ +epression/ psychosis/ an+ even +eliri"# D11/12E' Several *E s potentiate 2*B*er$ic ne"rotrans#ission/ either by interactin$ &ith 2*B** receptors or by #o+i,yin$ the activity o, en;y#es an+ transporters involve+ in the t"rnover o, 2*B* (@i$' 1)' Enhance#ent o, 2*B*er$ic ne"rotrans#ission is consi+ere+ to be a pri#ary #echanis# o, action ,or barbit"rates/ vi$abatrin (V2B)/ stiripentol (S:.)/ an+ tia$abine (:2B)' )ob"st 2*B*er$ic e,,ects/ ho&ever/ are also +isplaye+ by other co#po"n+s/ s"ch as topira#ate (:.-) an+ valproate (V.*) (:able 1)' 2'2' 2l"ta#ate trans#ission :he role o, $l"ta#ater$ic +ys,"nction in the pathophysiolo$y o, #oo+ an+ behavioral +isor+ers has $aine+ attention only in recent years' 2l"ta#ater$ic ne"rotrans#ission is an i#portant co#ponent in the stress<responsive casca+e o, events "lti#ately lea+in$ to hippoca#< pal an+ cortical alterations associate+ &ith #oo+ +isor+ers D131CE' Stress increases e9tracell"lar $l"ta#ate concentrations D16E an+ alters $l"ta#ate receptor bin+in$ pro=les an+ s"b"nit e9pression in several brain re$ions D1M/1JE' * n"#ber o, st"+ies ,o"n+ that $l"ta#ate levels are increase+ in the plas#a o, patients &ith #oo+ +isor+ers D19/20E' @"rther#ore/ psychotropic +r"$s can alter the bin+in$ pro=le o, $l"ta< #ate receptors D1CE/ an+ several a$ents actin$ on $l"ta#ater$ic ne"ro< trans#ission e9ert positive e,,ects on #oo+ an+ behavior D9/1CE' 1nhibition o, $l"ta#ater$ic ne"rotrans#ission is the pri#ary or secon+ary #echanis# o, action ,or a n"#ber o, *E s (:able 1)/ b"t it is o, relevance ,or ,elba#ate (@7B)/ la#otri$ine (7:2)/ an+ :.(@i$' 1)' 2'3' Volta$e<$ate+ so+i"# channels :here has been a ten+ency to investi$ate the role o, ne"rotrans< #itter syste#s in the pathophysiolo$y o, #oo+ an+ behavioral

+isor+ers D21/22E/ &hereas other syste#s/ s"ch as +ist"rbances in so+i"# an+ calci"# transport/ have been e9a#ine+ to a lesser e9tent D22E' 0evertheless/ evi+ence that so+i"# ho#eostasis is altere+ in #oo+ +isor+ers e9ists' Early st"+ies ,o"n+ that erythrocyte an+ &hole bo+y intracell"lar so+i"# concentrations are increase+ in patients &ith +epression an+ bipolar +isor+er an+ ret"rn to nor#al levels &ith recovery D23/24E' @"rther#ore/ several e,,ective #oo+<stabili;in$ an+ anti+epressant treat#ents re+"ce intracell"lar so+i"# concentrations or inhibit/ thro"$h bloc>a+e o, volta$e<$ate+ so+i"# channels/ so+i"# inO"9 D2CE' 5, note/ bloc>a+e o, volta$e<$ate+ so+i"# channels also res"lts in inhibition o, $l"ta#ate release D26E/ &hich is itsel, associate+ &ith positive e,,ects on #oo+ an+ behavior' -any *E s act pri#arily as so+i"# channel bloc>ers (:able 1 an+ @i$' 1)/ incl"+in$ carba#a;epine (CBT)/ phenytoin (.K:)/ o9carba;epine (5VC)/ eslicarba;epine acetate (ES7)/ lacosa#i+e (7C-)/ an+ r"=na#i+e ()3@)' 5, note/ bloc>a+e o, volta$e<$ate+ so+i"# channels is also an i#portant #echanis# o, action ,or 7:2/ @7B/ :.-/ an+ ;onisa#i+e (T0S)' 2'4' Volta$e<$ate+ calci"# channels Volta$e<$ate+ calci"# channels are #"lti#eric proteins co#pose+ o, =ve co<asse#ble+ s"b"nits (W1/ W2/ X/ N/ an+ Y)/ &hich can be broa+ly classi=e+ into hi$h<volta$e<activate+ channels (,"rther s"b$ro"pe+ as 7</ )</ .(4</ an+ 0<types) an+ lo&< volta$e<activate+ channels (:<type)' Evi+ence that these channels/ partic"larly hi$h<volta$e< activate+ channels/ #ay be i#plicate+ in the pathophysiolo$y o, #oo+ +isor+ers e9ists' 2enetic variation in C*C0*1C/ a $ene enco+in$ the alpha 1C s"b"nit o, the 7<type volta$e<$ate+ calci"# channel/ has been associate+ &ith bipolar +isor+er/ +epression/ an+ schi;ophrenia D2ME' 1n so#e e9peri#ental #o+els/ volta$e<$ate+ calci"# channel anta$onists +isplay anti+epressant properties D2J/29E/ &hereas a$onists lea+ to +epressant<li>e e,,ects D30E' 1nhibition o, volta$e<$ate+ calci"# channels probably translates into a re+"ction in e9citatory ne"rotrans< #ission D31/32E/ &hich #ay be "lti#ately responsible ,or positive e,,ects on #oo+ an+ behavior' Ethos"9i#i+e (E:V) is a lo&<volta$e<activate+ :<type channel< bloc>er/ &hereas $abapentin (2B.) an+ pre$abalin (.2B) are hi$h< volta$e<activate+ channel bloc>ers thro"$h interaction &ith the W2 Y

:able 2 .ositive an+ ne$ative psychotropic properties o, *E s an+ their i#plications ,or the #ana$e#ent o, psychiatric co#orbi+ities in patients &ith epilepsy' *E s .sychotropic e,,ects :reat#ent reco##en+ations ,or psychiatric co#orbi+ities in patients &ith epilepsy .ositive -oo+ lability( bipolar +isor+er *n9iety epression *voi+ .sychosis

0e$ative @irst $eneration Barbit"rates epression Chil+ren an+ in+ivi+"als &ith intellect"al +isabilities% hyperactivity/ irritability/ an+ a$$ression .sychosis (partic"larly at hi$h ser"# levels) .sychosis Chil+ren/ el+erly an+ in+ivi+"als &ith intellect"al +isabilities% hyperactivity/ irritability/ an+ a$$ression .sychosis/ +epression Chil+ren% hyperactivity/ a$$ression/ an+ a$itation .sychosis/ +epression/ an+ irritability 1n+ivi+"als &ith intellect"al +isabilities% hyperactivity/ irritability/ an+ a$$ression *n9iety/ psychosis Chil+ren an+ in+ivi+"als &ith intellect"al +isabilities% hyperactivity/ a$$ression/ an+ irritability epression/ psychosis/ an+ irritability 1rritability 1rritability/ a$$ression/ +epression/ an+ psychosis Kyperactivity/ irritability/ an+ a$$ression epression

.henytoin Ethos"9i#i+e Ben;o+ia;epines

.ossible #oo+<stabili;in$ e,,ectsS *n9iolytic e,,ects

Consi+er

Consi+er

*voi+ *voi+

Secon+ $eneration

Carba#a;epine Valproate Vi$abatrin

-oo+<stabili;in$ e,,ects -oo+<stabili;in$ e,,ects

Consi+er Consi+er

*voi+

*voi+

Tonisa#i+e 7a#otri$ine

-oo+<stabili;in$ e,,ects .ossible #il+ anti+epressant e,,ectsS *n9iolytic e,,ects

Consi+er

*voi+

*voi+ Consi+er

*voi+

@elba#ate 2abapentin

*voi+ Consi+er

*voi+

:opira#ate

:ia$abine 59carba;epine 7evetiraceta# Stiripentol .re$abalin )"=na#i+e 7acosa#i+e Eslicarba;epine acetate )eti$abine

*nti<i#p"lsive e,,ects .ossible anti+epressant e,,ectsS .ossible #oo+<stabili;in$ e,,ectsS *n9iolytic e,,ects

*voi+

*voi+

Consi+er

*voi+ *voi+ Consi+er

*voi+ *voi+ *voi+

*voi+ *voi+

:hir+ $eneration

no e,,ects $enerally reporte+(no speci=c reco##en+ations' 1t sho"l+ be e#phasi;e+ that ,or so#e *E s/ partic"larly thir+<$eneration a$ents/ clinical e9perience is still very li#ite+'

#o+"latory site (:able 1)' Bloc>a+e o, volta$e<$ate+ calci"# channels is also an i#portant #echanis# ,or 7:2 an+ T0S (@i$' 1)' 2'C' 5ther #echanis#s :he serotoniner$ic syste# is &i+ely reco$ni;e+ to #o+"late a &i+e ran$e o, physiolo$ical ,"nctions/ incl"+in$ #oo+ an+ behavior' ecrease+ serotoniner$ic ne"rotrans#ission has been propose+ to play a >ey role in the pathophysiolo$y o, a,,ective +isor+ers/ an+ enhance#ent o, serotoniner$ic ne"rotrans#ission is the pri#ary #echanis# o, action ,or #any psychotropic a$ents D33/34E' *n in< crease in e9tracell"lar serotonin has been observe+ &ith V.* D3CE/ CBT D36E/ 5VC D3ME/ :.- D3JE/ an+ T0S in e9peri#ental #o+els D39E an+ in vitro ,or 7:2 D40E' :he +opa#iner$ic syste# has lon$ been lin>e+ &ith #oo+ an+ be< havioral +isor+ers' 1ncrease+ +opa#iner$ic ne"rotrans#ission appears to play a role in schi;ophrenia/ #ania/ an+ a$$ressive behavior/ &hereas +ecrease+ +opa#iner$ic ,"nction #ay be i#plicate+ in the pathophys< iolo$y o, +epression D9/41/42E' opa#iner$ic ne"rotrans#ission is a

#a!or tar$et ,or psychotropic a$ents D43E' *ntiepileptic +r"$s #ay also #o+"late +opa#iner$ic ,"nction' 1n e9peri#ental #o+els/ V.* sti#"lates brain +opa#ine t"rnover D44E/ &hereas CBT/ 5VC/ :.-/ an+ T0S increase e9tracell"lar +opa#ine levels D3M/3J/4CE' 1ncreasin$ evi+ence s"$$ests that #oo+ +isor+ers/ partic"larly bipolar +isor+er/ are associate+ &ith a +isr"ption in #echanis#s an+ ,actors that $overn cell s"rvival an+ ne"ral plasticity D46E' :hese incl"+e inositol biosynthesis/ the cyclic a+enine #onophosphate (c<*-.) re< sponse ele#ent<bin+in$ protein/ the brain<+erive+ ne"rotrophic ,actor (B 0@)/ the $lyco$en synthase >inase<3 (2S6<3)/ the e9tracell"lar si$nal<re$"late+ >inase path&ay/ the arachi+onic aci+ path&ay/ the cytoprotective protein bcl<2/ an+ #ito$en<activate+ protein >inases D46/4ME' So#e #oo+ stabili;ers an+ anti+epressants #ay act on these ,actors/ "lti#ately atten"atin$ or reversin$ +isease<relate+ i#pair< #ents in ne"ronal plasticity/ ne"ro$enesis/ or cell s"rvival' :he #oo+ stabili;ers V.* an+/ to a lesser e9tent/ CBT +o +isplay si#ilar actions D4ME' 1n so#e patients &ith epilepsy/ s"++en s"ppression o, sei;"res #ay act as a tri$$er ,or the precipitation o, psychiatric sy#pto#s/ a

@i$' 1' -olec"lar tar$ets o, *E s' -o+i=e+ ,ro# D1J0E'

pheno#enon calle+ ,orce+ nor#ali;ation/ beca"se it can be associ< ate+ &ith nor#ali;ation o, the EE2 D4J/49E' :he psychiatric +isor+er #ost co##only associate+ &ith ,orce+ nor#ali;ation is psychosis/ b"t other #ani,estations/ s"ch as hypo#ania(#ania/ +epression/ an+ an9iety/ have been +escribe+ DC0E' .ost"late+ "n+erlyin$ #echanis#s incl"+e on$oin$ epileptic activity in li#bic str"ct"res/ inhibition s"rro"n+in$ the epileptic ,oc"s/ an+ altere+ balance bet&een e9cit< atory an+ inhibitory ne"rotrans#ission DC1E' @orce+ nor#ali;ation has been reporte+ &ith #ost *E s an+ #ay/ at least in part/ e9plain &hy certain *E s have para+o9ical e,,ects in epilepsy co#pare+ &ith other in+ications (e'$'/ e9acerbatin$ #oo+ +ys,"nction in pa< tients &ith epilepsy vs' i#provin$ a,,ective +isor+ers in psychiatric pop"lations)' 3' @irst $eneration *E s 3'1' Barbit"rates Barbit"rates/ &hich potentiate 2*B*er$ic ne"rotrans#ission by actin$ as positive allosteric #o+"lators o, 2*B** receptors (@i$' 1)/ carry an increase+ ris> ,or a variety o, a+verse psychiatric e,,ects (:able 2)' .atients ta>in$ phenobarbital (.B) have been sho&n to be associate+ &ith a hi$h prevalence o, #a!or +epressive +isor+er (40F) an+ s"ici+al i+eation (4MF) DC2E' 1n a cross<sectional st"+y/ the "se o, pri#i+one (.)-) &as associate+ &ith a 4'0J<,ol+ (9CF con=+ence interval% 2'09M'9J) increase+ ris> o, sy#pto#s o, +epres< sion DC3E' * lon$ history o, e9pos"re to barbit"rates #ay carry the $reatest ris> o, +epression/ partic"larly in the settin$ o, polytherapy an+ a personal or ,a#ily history o, a,,ective +isor+ers DME' 1n chil+ren an+ in+ivi+"als &ith learnin$ +isabilities/ the "se o, barbit"rates can

also in+"ce a syn+ro#e characteri;e+ by inso#nia/ hyperactivity/ i#p"lsiveness/ an+ a$$ressive behavior D10/C4E/ si#ilar to that +e< scribe+ &ith ben;o+ia;epines D11E' 3'2' .henytoin .henytoin is an establishe+ *E &ith a rob"st capacity to bin+ to an+ prolon$ the inactivation o,/ #a##alian/ volta$e<$ate+ so+i"# channels' S#all ran+o#i;e+ st"+ies s"$$est that .K: #ay be "se,"l in the treat< #ent o, bipolar +isor+er (ac"te therapy ,or #anic episo+es DCCE an+ #aintenance treat#ent DC6E)/ #a!or +epressive +isor+er DCME/ an+ i#p"lsive a$$ression DCJE' 1n one o, these st"+ies/ 29 patients &ith i#p"lsive a$$ression &ere ran+o#i;e+ to .K: 300 #$(+ay (n U M)/ CBT 4C0 #$(+ay (n U M)/ V.* MC0 #$(+ay (n U M)/ an+ placebo (n U J) ,or 6 &ee>s DCJE' :he a$$ression score/ a $lobal severity in+e9 ,ro# the 5vert *$$ression Scale/ &as lo&er &ith .K: an+ V.* co#pare+ &ith placebo (p U 0'001 ,or each co#parison)/ &hereas no si$ni=cant +i,,erences &ere ,o"n+ bet&een CBT an+ placebo' 7ar$er st"+ies/ ho&ever/ are reG"ire+ to con=r# the e,,ectiveness o, .K: in these con+itions DC9E' .henytoin has been rarely associate+ &ith ne$ative e,,ects on #oo+ DME' :o9ic plas#a concentrations/ ho&ever/ have been associ< ate+ &ith +eliri"#/ a$itate+ psychosis/ an+ a pec"liar syn+ro#e charac< teri;e+ by lethar$y/ ata9ia/ ophthal#ople$ia/ invol"ntary #ove#ents/ an+ para+o9ical sei;"res D6062E' 3'3' Ethos"9i#i+e Ethos"9i#i+e acts pri#arily by bloc>in$ :<type volta$e<$ate+ cal< ci"# channels' So#e a"thors +escribe+ the occ"rrence o, psychotic

episo+es +"rin$ E:V therapy/ characteri;e+ by an9iety/ +epression/ vis"al an+ a"+itory hall"cinations/ an+ inter#ittent i#pair#ent o, conscio"sness D63/64E' :hese episo+es appeare+ ,ollo&in$ cessation o, sei;"res an+ nor#ali;ation o, the EE2 an+ resolve+ &ith the +is< contin"ation o, the *E an+ sei;"re rec"rrence' :his pheno#enon/ as +isc"sse+ previo"sly/ has been ter#e+ ,orce+ nor#ali;ation DC0E' 3'4' Carba#a;epine * prototypical so+i"# channel<bloc>in$ *E / CBT is approve+ by the @oo+ an+ r"$ *+#inistration (@ *) ,or the treat#ent o, ac"te #anic an+ #i9e+ episo+es o, bipolar 1 +isor+er D6CE' 1n t&o #"lticen< ter/ ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+ trials/ 443 bipolar +isor+er patients &ith #anic or #i9e+ episo+es &ere ran+o#i;e+ to Oe9ible<+ose (2001600 #$(+ay) e9ten+e+<release CBT (n U 22C) or placebo (n U 220) ,or a 3<&ee> perio+ D66/6ME' 1n both st"+ies/ the i#prove#ent in the Zo"n$ -ania )atin$ Scale score (the pri#ary e,=cacy en+ point) &as $reater &ith CBT treat#ent than &ith placebo (=rst st"+y/ p U 0'032I secon+ st"+y/ p b 0'001)' Carba#a;epine appears to be e,,ective ,or #aintenance treat#ent o, bipolar +isor+er D4ME/ altho"$h to a lesser e9tent co#pare+ &ith lithi"# D6J/69E' Ko&ever/ CBT has been s"$$este+ to be a better alternative ,or atypical #ani,estations o, bipolar +isor+er/ s"ch as rapi+ cyclin$ co"rse/ #oo+<incon$r"ent +el"sions/ or other co#orbi+ psychiatric(ne"rolo$ic con+itions DM0E' Carba#a;epine #ay also be e,< ,ective in "nipolar +epression DM1E/ &hereas its "tility in schi;ophrenia is still "ncertain DM2E' *+verse psychiatric e,,ects are rarely reporte+ in epilepsy' 3'C' Valproate *ltho"$h its pri#ary #echanis# o, action is yet to be i+enti=e+/ evi+ence that V.* raises brain levels o, 2*B* e9ists' :his #ay occ"r by actin$ at +i,,erent sta$es o, the #etabolis# o, 2*B*% i) inhibition o, 2*B* transa#inase/ ii) inhibition o, s"ccinic se#ial+ehy+e +ehy< +ro$enase/ an+ iii) activation o, $l"ta#ic aci+ +ecarbo9ylase DM3E' 1t sho"l+ be note+/ ho&ever/ that other #echanis#s have been lin>e+ to V.*/ s"ch as inhibition o, $l"ta#ater$ic ne"rotrans#ission/ inhibi< tion o, :<type calci"# c"rrents/ an+/ possibly/ bloc>a+e o, volta$e< $ate+ so+i"# channels DM3/M4E' Valproate has also been sho&n to e9ert epi$enetic e,,ects by inhibitin$ histone +eacetylase activity DMCE' 5verall/ each o, these #echanis#s co"l+ contrib"te to its psycho< tropic properties (:able 2)' Valproate is an e,,ective #oo+ stabili;er/ approve+ by the @ * ,or the treat#ent o, ac"te #ania D4ME' *ltho"$h it has no #aintenance in+ication in bipolar +isor+er/ it is consi+ere+ a =rst<line a$ent ,or #aintenance treat#ent as &ell DM6/MME' * C2< &ee>/ #"lticenter/ ran+o#i;e+/ +o"ble<blin+/ parallel<$ro"p trial co#pare+ V.* (n U 1JM)/ lithi"# (n U 90)/ an+ placebo (n U 92) ,or #ainte< nance treat#ent in bipolar +isor+er DMJE' :he ti#e to +evelop#ent o, any #oo+ episo+e +i+ not +i,,er si$ni=cantly across the $ro"ps/ b"t a tren+ ,avore+ V.* over lithi"# (p U 0'06)' :he #e+ian ti#es to C0F s"rvival &itho"t any #oo+ episo+e &ere 40 &ee>s ,or V.*/ 24 &ee>s ,or lithi"#/ an+ 2J &ee>s ,or placebo' Valproate e9erts ben< e=cial e,,ects on several behavioral proble#s/ s"ch as hostility/ i#p"lsivity/ an+ a$$ression/ &hich #ay arise in +i,,erent clinical con< te9ts DM9E' 5n the contrary/ the inci+ence o, a+verse psychiatric e,,ects in patients &ith epilepsy is ne$li$ible' 4' Secon+ $eneration *E s 4'1' Vi$abatrin Vi$abatrin irreversibly inhibits 2*B* transa#inase/ the en;y#e responsible ,or +e$ra+in$ 2*B* to s"ccinic aci+ se#ial+ehy+e (@i$' 1)/ "lti#ately res"ltin$ in prolon$e+ elevation o, brain 2*B*

levels' -oo+ an+ behavior chan$es are i#portant a+verse e,,ects o,

V2B (:able 2)' * #eta<analysis o, +o"ble<blin+/ placebo<controlle+ a+!"nctive treat#ent trials in a total o, M1M a+"lt patients &ith +r"$<resistant partial epilepsy/ sho&e+ that V2B/ co#pare+ &ith pla< cebo/ is associate+ &ith a hi$her inci+ence o, +epression (12'1F vs' 3'CF/ p b 0'001) an+ psychosis (2'CF vs' 0'3F/ p U 0'02J) DJ0E' epres< sion &as typically #il+/ an+ psychosis $enerally i#prove+ ,ollo&in$ +ose a+!"st#ent or +iscontin"ation o, V2B or a,ter antipsychotic treat#ent' 1n #onotherapy trials/ the inci+ence o, +epression appears to be lo&er ([ CF) DJ1E' 1n pe+iatric pop"lations/ "p to 14'2F o, patients receivin$ V2B +evelop behavioral chan$es/ incl"+in$ hyper>inesia/ a$$ression/ a$itation/ an+ inso#nia' )is> ,actors ,or +evelopin$ a+verse psychiatric e,,ects +"rin$ V2B therapy incl"+e hi$h startin$ an+ #ain< tenance +oses/ a past psychiatric history an+ a severe ,or# o, epilepsy DJ2/J3E' 4'2' Tonisa#i+e Tonisa#i+e is a secon+<$eneration *E &ith lon$stan+in$ e9perience in \apan an+ 6orea/ an+ &hich acts pre+o#inantly thro"$h bloc>a+e o, volta$e<$ate+ so+i"# channels an+ inactivation o, volta$e<$ate+ :<type calci"# channels DJ4E' 5ther #echanis#s/ ho&ever/ appear to be in< volve+' Tonisa#i+e bin+s to the 2*B*< ben;o+ia;epine receptor co#ple9 DJCE/ elevates brain levels o, 2*B* DJ6E/ re+"ces e9tracell"lar release o, $l"ta#ate DJME/ an+ inhibits carbonic anhy+rase DJ4E' :his broa+ #echa< nistic pro=le #ay "n+erlie the variety o, e,,ects o, this *E on #oo+ an+ behavior' * n"#ber o, "ncontrolle+ st"+ies s"$$est that T0S #ay be e,,ective in the treat#ent o, bipolar +isor+er DJJ/J9E' :hese =n+in$s/ ho&ever/ &ere not con=r#e+ in a recent #"lticenter/ ran+o#i;e+/ +o"ble< blin+/ placebo<controlle+ trial D90E' Conversely/ in patients &ith epilepsy receivin$ T0S/ the occ"rrence o, a+verse psychiatric e,,ects #ay not be "nco##on (:able 2)' 1n a sin$le<center st"+y o, C44 patients/ the inci+ence o, a+verse psychi< atric e,,ects severe eno"$h to be associate+ &ith +iscontin"ation o, T0S &as 6'9F D91E' :he #ost co##on reason ,or +iscontin"ation &as +epression (n U 11)/ ,ollo&e+ by a$$ressive behavior (n U J)/ psychosis (n U 6)/ an+ irritability (n U C)' )is> ,actors ,or +iscontin"a< tion +"e to a+verse psychiatric e,,ects &ere past psychiatric history (p U 0'00C)/ sy#pto#atic $enerali;e+ epilepsy (p U 0'02M)/ an+ lo&er #a9i#"# T0S ser"# concentration (#ean U 1M'9 #$(7 vs' 34'M #$(7/ p b 0'001)' 4'3' 7a#otri$ine 7a#otri$ine has in+irect anti$l"ta#ater$ic e,,ects by actin$ at volta$e<$ate+ so+i"# channels to stabili;e ne"ronal #e#branes an+ $l"ta#ate release D92/93E' 7a#otri$ine has also been sho&n to #o+"< late calci"# con+"ctance involve+ in the release o, e9citatory a#ino aci+s in the cortico<striatal path&ay D94E an+ to a,,ect potassi"# con+"ctance D9CE' 1t #ay also increase the pro+"ction o, >yn"renic aci+/ an en+o$eno"s anta$onist at the $lycine bin+in$ site on the 0- * receptor D96E' 7:2 is @ *<approve+ ,or the #aintenance treat< #ent o, bipolar 11 +isor+er to prevent the occ"rrence o, #oo+ episo+es (+epression or hypo#ania) D9ME' Ko&ever/ 7:2 appears to be #ore e,,ective in preventin$ relapse o, +epression than #ania or hypo#a< nia D9JE' 7a#otri$ine #ay also be e,,ective in "nipolar +epression D99E/ at least in patients &ith epilepsy D100E/ &hereas its "se,"lness in schi;ophrenia is still "ncertain D101/102E' 7a#otri$ine has also been sho&n to have a bene=cial e,,ect on behavioral proble#s/ s"ch as i#p"lsivity an+ a$$ression D103/104E' * ,e& reports s"$$este+ that 7:2 #i$ht in+"ce behavioral prob< le#s in intellect"ally +isable+ patients &ith epilepsy' 1n a st"+y o, 19 patients/ 9 +isplaye+ a$$ressive behavior an+ 4 sho&e+ behavioral proble#s other than a$$ression ,ollo&in$ the intro+"ction o, 7:2 D10CE' Ko&ever/ it is "nclear &hether these behavioral proble#s/ at least in so#e patients/ co"l+ have been the res"lt o, the so<calle+ release pheno#enon D106E' 1n ,act/ in in+ivi+"als &ith intellect"al

+isabilities/ e,,ective treat#ents &ith a lo& se+ative potential #ay re< s"lt in increase+ alertness an+ sel,<assertion that #ay be #isinterprete+ as a+verse behavioral e,,ects' 4'4' @elba#ate *ltho"$h actin$ on a variety o, tar$ets/ @7B e9hibits rob"st anti$l"ta#ater$ic properties' :hese appear to be #e+iate+ by #o+"< lation o, strychnine<insensitive $lycine receptors associate+ &ith 0<#ethyl< <aspartate (0- *) receptors D10ME' @elba#ate is $enerally consi+ere+ a psycho<activatin$ a$ent D10JE' 1ts "se has been associate+ &ith i#prove#ents in alertness/ attention/ concentration/ as &ell as in social/ intellect"al/ an+ #otor ,"nctionin$ D10J/109E' 1ts a+verse psychiatric event pro=le is also consistent &ith an activatin$ pro=le' 1n a ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+/ parallel<$ro"p/ #onotherapy trial o, 40 patients &ith partial an+ secon+arily $enerali;e+ sei;"res "n+er$oin$ pres"r$ical eval"ation/ 6 o, the 21 @7B<treate+ patients &ith+re& ,ro# the st"+y +"e to treat#ent< e#er$ent a+verse e,,ects/ incl"+in$ psychosis/ an9iety/ sleepin$ +i,=< c"lties/ ab+o#inal +isco#,ort/ an+ orob"ccal +ys>inesia D110E' 4'C' 2abapentin 2abapentin #o+"lates calci"# c"rrents by bin+in$ to the W2 Y s"b"nit o, volta$e<$ate+ calci"# channels D1E' * n"#ber o, st"+ies s"$$este+ that 2B. #ay have an9iolytic properties DCE' 1n a +o"ble< blin+/ placebo<controlle+/ parallel<$ro"p trial/ 69 patients &ith social phobia &ere ran+o#i;e+ to Oe9ible<+ose (9003600 #$(+ay) 2B. (n U 34) or placebo (n U 3C) ,or 14 &ee>s D111E' Co#pare+ &ith place< bo/ 2B. &as associate+ &ith a si$ni=cant re+"ction in sy#pto#s o, so< cial phobia as #eas"re+ by +i,,erent patient< an+ physician<co#plete+ scales/ incl"+in$ the 7iebo&it; Social *n9iety Scale/ the Brie, Social .hobia Scale an+ the Social .hobia 1nventory' 1nitial open<label st"+ies s"$$este+ that 2B. co"l+ be e,,ective in the treat#ent o, bipolar +isor< +er D4ME' Ko&ever/ a ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+/ a++<on trial ,aile+ to +e#onstrate the s"periority o, 2B. over placebo in the ac"te therapy o, bipolar #ania D112E' Si#ilar res"lts &ere obtaine+ in patients &ith re,ractory bipolar or "nipolar #oo+ +isor+ers D113E' * s#all/ ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+ trial s"$$este+ that a+!"nctive 2B. #ay be "se,"l in #aintenance treat#ent o, bipolar +isor+er D114E/ b"t lar$er st"+ies are reG"ire+' :here are a ,e& reports s"$$estin$ that/ in chil+ren an+ patients &ith severe intellect"al +isabilities/ 2B. #ay in+"ce behavioral prob< le#s/ s"ch as hyperactivity an+ a$$ression D11C/116E' :hese =n+in$s/ ho&ever/ have not been con=r#e+ by other a"thors D106E' 4'6' :opira#ate :opira#ate is an *E &ith broa+<spectr"# e,=cacy/ an+ &hich acts on several #olec"lar tar$ets (:able 1)' 1n a++ition to potentiatin$ 2*B*er$ic ne"rotrans#ission/ :.- inhibits volta$e< $ate+ so+i"# an+ calci"# channels/ >ainate(W<a#ino<3< hy+ro9y<C<#ethyliso9a;ole< 4<proprionic aci+ (*-.*)<type $l"ta#ate receptors/ an+ carbonic anhy+rase' :he variety o, #echanis#s #ay e9plain &hy :.- has #i9e+ e,,ects on #oo+ an+ behavior D10JE (:able 2)' 1n patients &ith epilepsy/ :.- has been associate+ &ith a n"#ber o, ne$ative e,,ects on #oo+ an+ behavior' 1n a st"+y o, 431 consec"< tive patients/ a+verse psychiatric e,,ects +evelope+ in 103 (23'9F) D11ME' 1n partic"lar/ 46 (10'MF) patients e9perience+ +epression/ 16 (3'MF) psychotic sy#pto#s/ 24 (C'MF) a$$ressive behavior/ an+ 1M (3'9F) other behavioral proble#s' 1+enti=e+ ris> ,actors incl"+e+ hi$h startin$ +oses an+ rapi+ titration sche+"les/ a ,a#ily or personal psychiatric history/ a ,a#ily history o, epilepsy/ a personal history o, ,ebrile conv"lsions/ hippoca#pal sclerosis/ an+ tonic<atonic sei;"res

D11M/11JE'

5n the other han+/ there is evi+ence in the psychiatric literat"re that :.- #ay be e,,ective in the treat#ent o, #a!or +epression' 1n a 10<&ee>/ ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+ trial o, 64 pa< tients &ith #a!or +epressive +isor+er/ :.- 200 #$(+ay #onotherapy &as associate+ &ith a 1MF i#prove#ent in the Ka#ilton epression )atin$ Scale scores (,ro# 23'1 to 19'2) co#pare+ &ith a 4F i#prove< #ent &ith placebo (,ro# 22'9 to 22'0I p U 0'02) D119E' Si#ilar res"lts &ere ,o"n+ ,or a++<on :.- in treat#ent<resistant #a!or +epressive +isor+er D120E' :opira#ate &as also ,o"n+ to be e,,ective ,or an$er an+ a$$ression associate+ &ith +epression D119E or bor+erline person< ality +isor+er D121/122E/ &hereas +ata in schi;ophrenia are conOictin$ D12312CE' espite initial reports s"$$estin$ that :.- can be e,,ective in bipolar an+ post<tra"#atic stress +isor+ers/ several ran+o#i;e+ con< trolle+ trials ,aile+ to +e#onstrate its s"periority co#pare+ &ith place< bo D126129E' .reli#inary +ata s"$$est so#e e,=cacy in obsessive co#p"lsive +isor+er DCE an+ eatin$ +isor+ers D130E' :he psychotropic potential o, :.- is li>ely to be lar$e an+ poly< #orpho"s D131E' @"rther st"+ies are +e=nitely nee+e+' 4'M' :ia$abine :ia$abine potentiates 2*B*er$ic ne"rotrans#ission by selectively inhibitin$ the 2*:<1 2*B* transporter/ &hich is responsible ,or the "pta>e o, 2*B* into ne"rons an+ s"rro"n+in$ $lial cells a,ter synap< tic release (@i$' 1)' ata on the psychotropic pro=le o, :2B are contro< versial' *ltho"$h case series an+ ,e& open<label st"+ies s"$$est that this *E #ay have bene=cial or no e,,ects on #oo+ an+ an9iety D132134E/ the inci+ence o, #oo+ +isor+ers across =ve ran+o#i;e+/ +o"ble<blin+/ placebo< controlle+/ a++<on trials &as hi$her in patients ta>in$ :2B co#pare+ &ith those on placebo (CF vs' 1F) D13CE' 0ervo"sness &as also #ore co##on &ith :2B than placebo (12F vs' 3F)D13CE' 0evertheless/ psychiatric proble#s appear to be #il+ to #o+erate/ occ"r +"rin$ titration/ an+ abate spontaneo"sly' :he ris> o, :2B<in+"ce+ psychiatric proble#s #ay be increase+ in patients &ith a personal history o, #oo+ +isor+ers DME' 4'J' 59carba;epine 59carba;epine is a 10<>eto analo$"e o, CBT an+ acts pre+o#inantly on volta$e<$ate+ so+i"# channels (:able 1)' 1nitial s#all/ "n+erpo&< ere+/ placebo<"ncontrolle+ st"+ies s"$$este+ that 5VC #ay be "se,"l in the ac"te therapy o, bipolar #ania/ b"t concl"sive evi+ence is lac>in$ D4ME' -oreover/ a ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+ trial in yo"n$ patients &ith #ania ,aile+ to +etect si$ni=cant +i,,erences be< t&een 5VC an+ placebo D136E' 8hether 5VC is e,,ective in the ac"te treat#ent o, bipolar +epression or the #aintenance treat#ent o, bipo< lar +isor+er also re#ains to be +eter#ine+ D4M/13M/13JE' 5n the other han+/ preli#inary evi+ence s"$$ests that 5VC #ay e9ert bene=cial e,,ects on behavioral +isor+ers/ partic"larly i#p"lsive a$$ression D139E' 1n patients &ith epilepsy/ 5VC is $enerally consi+ere+ to pose a lo& ris> ,or a+verse psychiatric e,,ects D140E (:able 2)' 4'9' 7evetiraceta# :he #echanis# o, action o, levetiraceta# (7EV) +i,,ers ,ro# that o, c"rrently available *E s an+ appears to be #e+iate+ by bin+in$ to the synaptic vesicle protein SV2* D141E' :his bin+in$ is tho"$ht to res"lt in an inhibition o, ne"rotrans#itter release ,ro# the en+ ter#inals D142E' 7evetiraceta# &as initially post"late+ to have #oo+<stabili;in$ an+ an9iolytic properties D143/144E' Ko&ever/ t&o ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+ trials ,aile+ to +e#on<

strate the s"periority o, 7EV over placebo in the treat#ent o, bipolar +epression D14CE an+ $enerali;e+ social an9iety +isor+er D146E' * ne$ative trial has also been reporte+ in i#p"lsive a$$ression D14ME' -oo+ an+ behavioral proble#s have been reporte+ in patients &ith epilepsy (:able 2)' 1n a sin$le<center st"+y o, C1M consec"tive

patients treate+ &ith 7EV/ C3 (10'1F) e9perience+ a+verse psychiatric e,,ects D14JE' :hirteen (2'CF) patients +evelope+ +epression/ 6 (1'2F) psychotic sy#pto#s/ 19 (3'CF) a$$ressive behavior/ 12 (2'3F) e#o< tional lability/ an+ 3 (0'6F) other behavioral proble#s/ s"ch as a$ita< tion/ an$er(hostile behavior/ an+ personality chan$es' )is> ,actors ,or +evelopin$ a+verse psychiatric e,,ects incl"+e+ a history o, ,ebrile conv"lsions/ a history o, stat"s epileptic"s/ an+ a previo"s psychiatric history D14JE' 8hether a ,aster titration sche+"le is also a ris> ,actor is controversial D14J/149E' 5, note/ a recent st"+y ,o"n+ an association bet&een $enetic variations in +opa#iner$ic activity an+ the ris> ,or a+verse psychiatric e,,ects +"rin$ 7EV therapy D1C0E' 4'10' Stiripentol Stiripentol is a secon+<$eneration *E &ith proven e,=cacy in severe #yoclonic epilepsy in in,ancy ( ravet syn+ro#e) D1C1E' Stiripentol potentiates 2*B*er$ic ne"rotrans#ission/ possibly by actin$ +irectly on 2*B** receptors as a positive allosteric #o+"lator D1C2E (@i$' 1)' Stiripentol can ca"se a+verse behavioral e,,ects/ s"ch as hyperactivity/ irritability/ a$$ressiveness/ an+ inso#nia' 1n a ran< +o#i;e+/ +o"ble<blin+/ placebo<controlle+ trial/ +ro&siness/ hyperac< tivity/ a$$ressiveness/ an+ inso#nia &ere reporte+ in 91F o, patients ta>in$ S:. an+ 2CF o, those on placebo D1C3E' *ltho"$h the inci+ence o, behavioral a+verse e,,ects is relatively hi$h/ so#e o, these can be ascribe+ to phar#aco>inetic(phar#aco+yna#ic interactions &ith conco#itant *E s an+ can be #ana$e+ by +ose a+!"st#ents D1C4E' *s ,or 7:2/ the so<calle+ release pheno#enon #ay be observe+ D106E' 4'11' .re$abalin

D166E' 8ell<+esi$ne+ st"+ies are reG"ire+ to e9pan+ on these preli#inary =n+in$s' C'2' 7acosa#i+e 7acosa#i+e is a ne& *E &ith recent @ *< an+ E-*<approval as a+!"nctive therapy ,or a+"lts &ith ,ocal sei;"res D16ME' :he pri#ary #echanis# o, action o, 7C- consists in enhance#ent o, slo& inacti< vation o, volta$e<$ate+ so+i"# channels &itho"t any apparent action on ,ast inactivation/ a #echanis# that +i,,ers ,ro# that o, other so+i< "# channel<bloc>in$ *E s D16J/169E' *ltho"$h it re#ains controver< sial/ 7C- #ay also act on the collapsin response #e+iator protein (C)-.)<2/ &hich #ay be involve+ in a9onal o"t$ro&th an+ ne"ronal +i,,erentiation D16ME' :here is ins",=cient e9perience &ith this *E to +ra& any concl"sion re$ar+in$ its psychotropic pro=le' @"rther a+ hoc st"+ies are nee+e+' C'3' Eslicarba;epine acetate Eslicarba;epine acetate is a novel *E recently approve+ by the E-* as a+!"nctive therapy ,or a+"lts &ith ,ocal sei;"res/ &ith or &itho"t secon+ary $enerali;ation D16ME' Eslicarba;epine acetate is itsel, a pro<+r"$ ,or eslicarba;epine/ &hich is the S<enantio#er o, the active #onohy+ro9y<#etabolite o, 5VC D16M/1M0E' 7i>e 5VC/ ES7 acts pri#arily by bloc>in$ volta$e<$ate+ so+i"# channels' 8hether ES7 an+ 5VC share si#ilar psychotropic properties re#ains to be +eter#ine+' C'4' )eti$abine

Si#ilarly to 2B./ .2B is a li$an+ ,or the W2Y s"b"nit o, volta$e< $ate+ calci"# channels' Several ran+o#i;e+/ +o"ble<blin+/ placebo< controlle+ trials ,o"n+ that .2B is e,,ective in $enerali;e+ an9iety +isor+er an+ social an9iety +isor+er DC/1CC1CJE' 1n one o, these st"+ies/ 2M3 el+erly patients &ith $enerali;e+ an9iety +isor+er &ere ran+o#i;e+ in a 2%1 ratio to Oe9ible<+ose (1C0600 #$(+ay) .2B (n U 1MM) or placebo (n U 96) ,or J &ee>s D1CCE' .re$abalin &as associate+ &ith $reater i#prove#ent/ startin$ in the secon+ &ee> o, treat#ent/ in the Ka#ilton )atin$ Scale ,or *n9iety (K)S*) total scores co#pare+ &ith placebo (p b 0'0C)' 2reat< er i#prove#ents &ere also ,o"n+ in the K)S* psychic an+ so#atic an9< iety ,actors an+ in the Ka#ilton )atin$ Scale ,or +epression total scores' *ltho"$h a ,e& reports s"$$est that .2B #ay be e,,ective in other #oo+ +isor+ers D1C9/160E/ evi+ence ,ro# ran+o#i;e+ controlle+ trials is lac>in$' 1n patients &ith epilepsy/ .2B +oes not appear to have si$ni=cant ne$ative e,,ects on #oo+ or behavior D161E/ altho"$h +epression has been reporte+ in so#e patients D162E' C' :hir+ $eneration *E s C'1' )"=na#i+e )"=na#i+e is a novel *E recently approve+ by the @ * an+ the E"ropean -e+icines *$ency (E-*) as a+!"nctive treat#ent ,or sei;"res associate+ &ith 7enno92asta"t syn+ro#e in chil+ren a$e+ ] 4 years an+ a+"lts' )"=na#i+e #o+"lates the activity o, volta$e< $ate+ so+i"# channels/ principally via prolon$ation o, the inactive state o, the channel D163E' :he initial e9perience &ith )3@ yiel+e+ conOictin$ +ata re$ar+in$ its psychotropic pro=le' 1n a poole+ analysis o, sa,ety an+ tolerability +ata ,ro# M clinical st"+ies in epilepsy/ )3@ &as not associate+ &ith an increase+ ris> o, a+verse psychiatric e,,ects D164E' 5,,<label "se o, )3@ in t&o patients &ith re,ractory bipolar +isor+er res"lte+ in re+"ction o, +epressive/ an9iety/ an+ obsessive ,eat"res &ith #oo+ stabili;ation in one case an+ re+"ction in +epression/ an9iety/ bin$e eatin$/ an+ alcohol cravin$ &ith #oo+ stabili;ation in the secon+ case D16CE' 1n t&o other si#ilar patients/ ho&ever/ its "se res"lte+ in activation o, s"ici+al i+eation

)eti$abine ():2)/ also >no&n as e;o$abine in the 3'S'/ is a novel *E &ith recent @ *< an+ the E-*<approval as a+!"nctive therapy ,or a+"lts &ith ,ocal sei;"res' )eti$abine is a =rst<in<class a$ent in that it opens ne"ronal 6vM (6C04) volta$e<$ate+ potassi"# channels/ &hich stabili;e via -<c"rrent restin$ #e#brane potentials D1M1E' ata ,ro# ani#al #o+els s"$$est that ):2 #ay have #oo+< stabili;in$ an+ an9iolytic e,,ects D1M2/1M3E' :hese =n+in$s/ ho&ever/ have not yet been con=r#e+ in h"#ans' Sparse +ata are available on the inci+ence o, a+verse psychiatric e,,ects in patients &ith epilepsy' 1n three pivotal ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+ trials involvin$ ^ 1200 patients &ith +r"$<resistant epilepsy/ ):2/ &hen co#pare+ &ith placebo/ &as associate+ &ith a hi$her inci+ence o, con,"sional state (9F vs' 3F)/ psychotic sy#pto#s (1F vs' 0F)/ an+ vis"al(a"+itory hall"cina< tions (2F vs' b 1F) D1M41MME' -ost e,,ects +evelope+ +"rin$ the =rst ,e& &ee>s o, treat#ent an+ appeare+ to be relate+ to a rapi+ titration sche+"le D1MME' 6' 7i#itations o, c"rrent literat"re 1t sho"l+ be e#phasi;e+ that/ ,or the #a!ority o, *E s/ in,or#a< tion on #oo+ an+ behavioral e,,ects is either ina+eG"ate or #issin$' -oreover/ available investi$ations s",,er ,ro# a n"#ber o, #etho+o< lo$ical li#itations' -any observations co#e ,ro# case reports or "ncontrolle+ st"+ies' Beca"se psychiatric events can be relate+ to epilepsy itsel, rather than to its treat#ent/ establishin$ ca"see,,ect relationships can be proble#< atic' 5ne &ay to +eter#ine ca"sality is by sho&in$ +isappearance o, the a+verse event a,ter &ith+ra&in$ the s"specte+ precipitatin$ a$ent an+ re<appearance a,ter re<challen$e D1MJE' Ko&ever/ re<challen$e is "s"al< ly +i,=c"lt to !"sti,y on ethical $ro"n+s/ an+ s"ch st"+ies &o"l+ not nec< essarily in,or# abo"t the characteristics o, patients at ris>' ata ,ro# controlle+ trials also s",,er a n"#ber o, li#itationsI the #ost i#portant relates to the pa"city o, hea+<to<hea+ co#parisons "sin$ stan+ar+i;e+ assess#ent #etho+olo$y' 5ther li#itations o, controlle+ st"+ies in< cl"+e% (i) ,reG"ent "se o, an a++<on +esi$n/ so that any psychotropic

e,,ect co"l+ be attrib"table to phar#aco+yna#ic or phar#aco>inetic +r"$ interactionsI (ii) "se o, =9e+ +oses an+ titration sche+"les/ &hich o,ten +i,,er ,ro# those #ost co##only applie+ in clinical prac< ticeI (iii) e9cl"sion o, patients &ith psychiatric +isor+ers an+ other ris> $ro"psI an+ (iv) a ,ollo&<"p perio+ &hich #ay not be s",=cient to +etect e,,ects &ith a late onset D1M9E' 1n+ee+/ the ,act that the +ata on the psychotropic e,,ects o, *E s in epilepsy co#e ,ro# very hetero$< eno"s so"rces (i'e'/ case reports/ retrospective s"rveys/ observational st"+ies/ controlle+ clinical trials &ith +i,,erent +esi$ns an+ o"tco#e #eas"res) consi+erably li#its the possibility o, +ra&in$ +e=nite con< cl"sions abo"t the co#parative e,,ects o, in+ivi+"al co#po"n+s' M' Concl"sions *ntiepileptic +r"$s s"ppress sei;"res by actin$ on a variety o, #echanis#s an+ #olec"lar tar$ets involve+ in the re$"lation o, ne"< ronal e9citability' :hese incl"+e inhibitory (2*B*er$ic) an+ e9citato< ry ($l"ta#ater$ic) ne"rotrans#ission/ as &ell as ion (so+i"# an+ calci"#) con+"ctance thro"$h volta$e<$ate+ channels' Ko&ever/ these #echanis#s an+ tar$ets are also i#plicate+ in the re$"lation o, #oo+ an+ behavior/ &hich #ay e9plain &hy each *E is associate+ &ith speci=c psychotropic e,,ects' 5"r c"rrent "n+erstan+in$ o, the #echanis#s "n+erlyin$ #oo+ an+ behavior e,,ects o, *E s is ,ar ,ro# bein$ co#plete' @or so#e a$ents/ s"ch as 7EV or ):2/ &hich +o not act (or #ay only #ar$inally act) on the tra+itional tar$ets +escribe+ above/ #echanis#s responsi< ble ,or their psychotropic e,,ects are yet to be +iscovere+' 3n>no&n #echanis#s #ay also "n+erpin +i,,erences in psychotropic pro=les across a$ents &ith apparently si#ilar actions' 0ovel #olec"lar tar$ets/ s"ch as the synaptic vesicle protein SV2* or ne"ronal 6vM volta$e<$ate+ potassi"# channels/ &hose role in #oo+ an+ behavior has not been yet investi$ate+/ #ay acco"nt ,or speci=c psychotropic e,,ects' 1t is also note&orthy that >no&le+$e o, #oo+ an+ behavioral e,,ects o, *E s is either ina+eG"ate or co#pletely #issin$/ &ith available +ata bein$ obtaine+ ,ro# st"+ies &hich s",,er ,ro# #etho+olo$ical li#ita< tions' 8ell<+esi$ne+ investi$ations are "r$ently nee+e+' Better +e=nin$ psychotropic pro=les o, *E s &o"l+ ,"rther e9pan+ opport"nities to tailor treat#ent in patients &ith epilepsy an+ co"l+ potentially lea+ to i+enti=cation o, novel treat#ent strate$ies in psychiatric con+itions' )e,erences
D1E -"la -' 0e& antiepileptic +r"$s% #olec"lar tar$ets' Cent 0erv Syst *$ents -e+ Che# 2009I9%M9<J6' D2E \ohannessen 7an+#ar> C/ \ohannessen S1' .har#acolo$ical #ana$e#ent o, epilepsy% recent a+vances an+ ,"t"re prospects' r"$s 200JI6J%192C<39' D3E .er"cca ./ Carter \/ Vahle V/ 2illia# @2' *+verse antiepileptic +r"$ e,,ects% to&ar+ a clinically an+ ne"robiolo$ically relevant ta9ono#y' 0e"rolo$y 2009IM2% 1223<9' D4E Ettin$er *B' .sychotropic e,,ects o, antiepileptic +r"$s' 0e"rolo$y 2006I6M% 1916<2C' DCE -"la -/ .ini S/ Cassano 2B' :he role o, anticonv"lsant +r"$s in an9iety +isor+ers% a critical revie& o, the evi+ence' \ Clin .sychophar#acol 200MI2M% 263<M2' D6E Spina E/ .er"$i 2' *ntiepileptic +r"$s% in+ications other than epilepsy' Epileptic isor+ 2004I6%CM<MC' DME -"la -/ San+er \8' 0e$ative e,,ects o, antiepileptic +r"$s on #oo+ in patients &ith epilepsy' r"$ Sa, 200MI30%CCC<6M' DJE Sanacora 2/ Saricice> *' 2*B*er$ic contrib"tions to the pathophysiolo$y o, +epression an+ the #echanis# o, anti+epressant action' C0S 0e"rol isor+ r"$ :ar$ets 200MI6%12M<40' D9E Co#ai S/ :a" -/ 2obbi 2' :he psychophar#acolo$y o, a$$ressive behavior% a translational approach% part 1% ne"robiolo$y' \ Clin .sychophar#acol 2012I32% J3<94' D10E 7orin$ 8/ -arino S/ -ea+or 6\' 0e"ropsycholo$ical an+ behavioral e,,ects o, antiepilepsy +r"$s' 0e"ropsychol )ev 200MI1M%413<2C' D11E 5la!i+e / 7a+er -' epression ,ollo&in$ &ith+ra&al ,ro# lon$<ter# ben;o+ia;e< pine "se% a report o, ,o"r cases' .sychol -e+ 19J4I14%93M<40' D12E Ka"ser ./ evins>y 5/ e Bellis -/ :heo+ore 8K/ .ost )-' Ben;o+ia;epine &ith< +ra&al +eliri"# &ith catatonic ,eat"res' 5cc"rrence in patients &ith partial sei;"re +isor+ers' *rch 0e"rol 19J9I46%696<9'

D13E D14E D1CE

D16E

D1ME

D1JE

D19E

D20E

D21E

D22E D23E

D24E D2CE D26E

D2ME D2JE

D29E

D30E

D31E

D32E

D33E D34E D3CE

D36E

D3ME

D3JE

D39E D40E

D41E D42E D43E D44E

Sheline Z1' Kippoca#pal atrophy in #a!or +epression% a res"lt o, +epression< in+"ce+ ne"roto9icityS -ol .sychiatry 1996I1%29J<9' Sapols>y )-' 2l"cocorticoi+s an+ hippoca#pal atrophy in ne"ropsychiatric +isor+ers' *rch 2en .sychiatry 2000ICM%92C<3C' 6en+ell S@/ 6rystal \K/ Sanacora 2' 2*B* an+ $l"ta#ate syste#s as therape"tic tar$ets in +epression an+ #oo+ +isor+ers' E9pert 5pin :her :ar$ets 200CI9% 1C3<6J' Ba$ley \/ -o$ha++a# B' :e#poral +yna#ics o, $l"ta#ate e,O"9 in the pre,rontal corte9 an+ in the hippoca#p"s ,ollo&in$ repeate+ stress% e,,ects o, pretreat#ent &ith saline or +ia;epa#' 0e"roscience 199MIMM%6C<M3' 0o&a> 2/ 5r+&ay 2*/ .a"l 1*' *lterations in the 0<#ethyl< <aspartate (0- *) receptor co#ple9 in the ,rontal corte9 o, s"ici+e victi#s' Brain )es 199CI6MC% 1CM<64' Bartan"s; V/ *"bry \-/ .a$li"si S/ \e;ova / Ba,= \/ 6iss \T' Stress<in+"ce+ chan$es in #essen$er )0* levels o, 0<#ethyl< <aspartate an+ *-.* receptor s"b"nits in selecte+ re$ions o, the rat hippoca#p"s an+ hypothala#"s' 0e"ro< science 199CI66%24M<C2' *lta#"ra C*/ -a"ri -C/ @errara */ -oro *)/ H*n+rea 2/ Ta#berlan @' .las#a an+ platelet e9citatory a#ino aci+s in psychiatric +isor+ers' *# \ .sychiatry 1993I1C0%1M31<3' -a"ri -C/ @errara */ Boscati 7/ et al' .las#a an+ platelet a#ino aci+ concentra< tions in patients a,,ecte+ by #a!or +epression an+ "n+er O"vo9a#ine treat#ent' 0e"ropsychobiolo$y 199JI3M%124<9' 7erer B/ -acciar+i @' .har#aco$enetics o, anti+epressant an+ #oo+<stabili;in$ +r"$s% a revie& o, can+i+ate<$ene st"+ies an+ ,"t"re research +irections' 1nt \ 0e"ropsychophar#acol 2002IC%2CC<MC' Va&ter -./ @ree+ 8\/ 6lein#an \E' 0e"ropatholo$y o, bipolar +isor+er' Biol .sychiatry 2000I4J%4J6<C04' 0aylor 2\/ -c0a#ee KB/ -oo+y \.' Chan$es in erythrocyte so+i"# an+ potassi"# on recovery ,ro# a +epressive illness' Br \ .sychiatry 19M1I11J%219< 23' -en+els \/ @ra;er *' *lterations in cell #e#brane activity in +epression' *# \ .sychiatry 19M4I131%1240<6' El<-alla>h )S/ K",, -5' -oo+ stabili;ers an+ ion re$"lation' Karv )ev .sychiatry 2001I9%23<32' @arber 0B/ \ian$ V./ Kein>el C/ 0e##ers B' *ntiepileptic +r"$s an+ a$ents that inhibit volta$e<$ate+ so+i"# channels prevent 0- * anta$onist ne"roto9icity' -ol .sychiatry 2002IM%M26<33' Bhat S/ ao :/ :errillion CE/ et al' C*C0*1C (Ca(v)1'2) in the pathophysiolo$y o, psychiatric +isease' .ro$ 0e"robiol 2012I99%114' -o$ilnic>a E/ C;yra> */ -a! \' ihy+ropyri+ine calci"# channel anta$onists re+"ce i##obility in the #o"se behavioral +espair testI anti+epressants ,acilitate ni,e+ipine action' E"r \ .har#acol 19JMI13J%413<6' 2aleotti 0/ Bartolini */ 2helar+ini C' Bloc>a+e o, intracell"lar calci"# release in+"ces an anti+epressant<li>e e,,ect in the #o"se ,orce+ s&i##in$ test' 0e"rophar#acolo$y 2006IC0%309<16' Sinne$$er<Bra"ns -\/ Ket;ena"er */ K"ber 12/ et al' 1so,or#<speci=c re$"lation o, #oo+ behavior an+ pancreatic beta cell an+ car+iovasc"lar ,"nction by 2R 7<type Ca channels' \ Clin 1nvest 2004I113%1430<9' 4"intero \E/ ooley \/ .o#erlea" @/ K"ettl ./ 2erhar+t 2*' *#pero#etric #ea< s"re#ent o, $l"ta#ate release #o+"lation by $abapentin an+ 2R pre$abalin in rat neocortical slices% role o, volta$e<sensitive Ca alpha2+elta<1 s"b"nit' \ .har#acol E9p :her 2011I33J%240<C' ooley \/ -ies>e C*/ Boros>y S*' 1nhibition o, 6(R)<evo>e+ $l"ta#ate release ,ro# rat neocortical an+ hippoca#pal slices by $abapentin' 0e"rosci 7ett 2000I2J0%10M<10' Schloss ./ 8illia#s C' :he serotonin transporter% a pri#ary tar$et ,or anti+e< pressant +r"$s' \ .sychophar#acol 199JI12%11C<21' 6"p,er \/ @ran> E/ .hillips -7' -a!or +epressive +isor+er% ne& clinical/ ne"robi< olo$ical/ an+ treat#ent perspectives' 7ancet 2012I3M9%104C<CC' 8hitton .S/ 5res>ovic / \erne! B/ B"lat -' E,,ect o, valproic aci+ on C<hy+ro9ytrypta#ine t"rnover in #o"se brain' \ .har# .har#acol 19JCI3M% 199<200' ailey \8/ )eith -E/ Zan 4S/ 7i -Z/ \obe .C' Carba#a;epine increases e9tracel< 2R l"lar serotonin concentration% lac> o, anta$onis# by tetro+oto9in or ;ero Ca ' E"r \ .har#acol 199MI32J%1C3<62' Clinc>ers )/ S#ol+ers 1/ -e"rs */ Ebin$er 2/ -ichotte Z' Kippoca#pal +opa#ine an+ serotonin elevations as phar#aco+yna#ic #ar>ers ,or the anticonv"lsant e,=cacy o, o9carba;epine an+ 10/11<+ihy+ro<10<hy+ro9ycarba#a;epine' 0e"rosci 7ett 200CI390%4J<C3' Za#a#"ra S/ Ka#a$"chi :/ 5hoya#a 6/ et al' :opira#ate an+ ;onisa#i+e prevent para+o9ical into9ication in+"ce+ by carba#a;epine an+ phenytoin' Epilepsy )es 2009IJ4%1M2<J6' 5>a+a -/ Kirano :/ 6a&ata Z/ et al' Biphasic e,,ects o, ;onisa#i+e on serotoner$ic syste# in rat hippoca#p"s' Epilepsy )es 1999I34%1JM<9M' So"tha# E/ 6ir>by / Ki$$ins 2*/ Ka$an )-' 7a#otri$ine inhibits #onoa#ine "pta>e in vitro an+ #o+"lates C<hy+ro9ytrypta#ine "pta>e in rats' E"r \ .har#acol 199JI3CJ%19<24' iehl \/ 2ershon S' :he role o, +opa#ine in #oo+ +isor+ers' Co#pr .sychiatry 1992I33%11C<20' Bro&n *S/ 2ershon S' opa#ine an+ +epression' \ 0e"ral :rans# 2en Sect 1993I91%MC109' 0"tt \' :he role o, +opa#ine an+ norepinephrine in +epression an+ anti+epressant treat#ent' \ Clin .sychiatry 2006I6M(S"ppl' 6)%3<J' 7oscher 8/ Konac> ' Valproate an+ its #a!or #etabolite E<2<en<valproate in+"ce +i,,erent e,,ects on behavio"r an+ brain #onoa#ine #etabolis# in rats' E"r \ .har#acol 1996I299%61<M'

D4CE 5>a+a -/ 6ane>o S/ Kirano :/ et al' E,,ects o, ;onisa#i+e on +opa#iner$ic syste#' Epilepsy )es 199CI22%193<20C' D46E )o$a&s>i -*/ 7oscher 8' :he ne"robiolo$y o, antiepileptic +r"$s ,or the treat#ent o, nonepileptic con+itions' 0at -e+ 2004I10%6JC<92' D4ME 2r"n;e KC' *nticonv"lsants in bipolar +isor+er' \ -ent Kealth 2010I19%12M<41' D4JE 7an+olt K' .sychic +isor+ers in epilepsy' Clinical an+ electroencephalo$raphic research' tsch -e+ 8ochenschr 1962IJM%446<C2' D49E 6rishna#oorthy ES/ :ri#ble -)' @orce+ nor#ali;ation% clinical an+ therape"tic relevance' Epilepsia 1999I40(S"ppl' 10)%SCM<64' DC0E :ri#ble -)/ Sch#it; B' @orce+ nor#ali;ation an+ alternative psychoses o, epilepsy' .eters=el+% 8ri$htson Bio#e+ical ."blishin$ 7t+I 199J' DC1E -"la -' :he 7an+oltHs pheno#enon% an "p+ate' Epileptolo$ia 2010I1J%39<44' DC2E Brent */ Cr"#rine .6/ Var#a ))/ *llan -/ *ll#an C' .henobarbital treat#ent an+ #a!or +epressive +isor+er in chil+ren &ith epilepsy' .e+iatrics 19JMIJ0%909<1M' DC3E 7ope;<2o#e; -/ )a#ire;<Ber#"+e; \/ Ca#pillo C/ Sosa *7/ Espinola -/ )"i; 1' .ri#i+one is associate+ &ith interictal +epression in patients &ith epilepsy' Epilepsy Behav 200CI6%413<6' DC4E Vinin$ E./ -ellitis E / orsen --/ et al' .sycholo$ic an+ behavioral e,,ects o, antiepileptic +r"$s in chil+ren% a +o"ble<blin+ co#parison bet&een phenobar< bital an+ valproic aci+' .e+iatrics 19JMIJ0%16C<M4' DCCE -ishory */ Zaroslavs>y Z/ Bers"+s>y Z/ Bel#a>er )K' .henytoin as an anti#anic anticonv"lsant% a controlle+ st"+y' *# \ .sychiatry 2000I1CM%463<C' DC6E -ishory */ 8ino>"r -/ Bers"+s>y Z' .rophylactic e,,ect o, phenytoin in bipolar +isor+er% a controlle+ st"+y' Bipolar isor+ 2003IC%464<M' DCME 0e#ets B/ Bers"+s>y Z/ Bel#a>er )K' Controlle+ +o"ble<blin+ trial o, phenytoin vs' O"o9etine in #a!or +epressive +isor+er' \ Clin .sychiatry 200CI66%CJ6<90' DCJE Stan,or+ -S/ Kel,rit; 7E/ Con>lin S-/ et al' * co#parison o, anticonv"lsants in the treat#ent o, i#p"lsive a$$ression' E9p Clin .sychophar#acol 200CI13%M2<M' DC9E -"la -/ -onaco @' .henytoin an+ other hy+antoins% clinical e,=cacy an+ "se in psychiatric +isor+ers' 1n% 7evy )/ -attson )/ -el+r"# B/ .er"cca E/ e+itors' *ntiepileptic +r"$s' Cth e+' Balti#ore% 7ippincott 8illia# & 8il>insI 2002' p' 600<4' D60E -c7ellan 7/ S&ash -' Choreo<athetosis an+ encephalopathy in+"ce+ by phenytoin' Br -e+ \ 19M4I2%204<C' D61E Ch"a KC/ Ven>etas"bra#anian 0/ :an CB/ :!ia K' .ara+o9ical sei;"res in phenytoin to9icity' Sin$apore -e+ \ 1999I40%2M6<M' D62E Sch#it; B' .sychiatric syn+ro#es relate+ to antiepileptic +r"$s' Epilepsia 1999I40(S"ppl' 10)%S6C<M0' D63E @ischer -/ 6ors>!aer 2/ .e+ersen E' .sychotic episo+es in Taron+an treat#ent' E,,ects an+ si+e<e,,ects in 10C patients' Epilepsia 196CI6%32C<34' D64E )o$er \/ 2ran$eon K/ 2"ey! \/ 7ob K' .sychiatric an+ psycholo$ic e,,ects o, ethos"9i#i+e treat#ent o, epileptics' Enc_phale 196JICM%40M<3J' D6CE .ost )-/ 6etter :*/ 3h+e :/ Ballen$er \C' :hirty years o, clinical e9perience &ith carba#a;epine in the treat#ent o, bipolar illness% principles an+ practice' C0S r"$s 200MI21%4M<M1' D66E 8eisler )K/ 6alali *K/ 6etter :*' * #"lticenter/ ran+o#i;e+/ +o"ble<blin+/ placebo< controlle+ trial o, e9ten+e+<release carba#a;epine caps"les as #onotherapy ,or bipolar +isor+er patients &ith #anic or #i9e+ episo+es' \ Clin .sychiatry 2004I6C%4MJ<J4' D6ME 8eisler )K/ 6ec> \r .E/ S&ann *C/ C"tler *\/ 6etter :*/ 6alali *K' E9ten+e+< release carba#a;epine caps"les as #onotherapy ,or ac"te #ania in bipolar +isor+er% a #"lticenter/ ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+ trial' \ Clin .sychiatry 200CI66%323<30' D6JE 2reil 8/ 7"+&i$<-ayerho,er 8/ Era;o 0/ et al' 7ithi"# vers"s carba#a;epine in the #aintenance treat#ent o, bipolar +isor+ersa ran+o#ise+ st"+y' \ *,,ect isor+ 199MI43%1C1<61' D69E Karton$ E2/ -ole#an ./ Koo$+"in C*/ Broe>#an :2/ 0olen 8*' .rophylactic e,=cacy o, lithi"# vers"s carba#a;epine in treat#ent<naive bipolar patients' \ Clin .sychiatry 2003I64%144<C1' DM0E 2reil 8/ 6lein+ienst 0/ Era;o 0/ -"ller<5erlin$ha"sen B' i,,erential response to lithi"# an+ carba#a;epine in the prophyla9is o, bipolar +isor+er' \ Clin .sychophar#acol 199JI1J%4CC<60' DM1E Than$ T\/ :an 4)/ :on$ Z/ et al' :he e,,ectiveness o, carba#a;epine in "nipolar +epression% a +o"ble<blin+/ ran+o#i;e+/ placebo<controlle+ st"+y' \ *,,ect isor+ 200JI109%91<M' DM2E 7e"cht S/ 6isslin$ 8/ -c2rath \/ 8hite .' Carba#a;epine ,or schi;ophrenia' Cochrane atabase Syst )ev 200M%C 0012CJ' DM3E Bo"r$eois B@ ' Valproate' 1n% Shorvon S/ .er"cca E/ En$el \r \/ e+itors' :he treat< #ent o, epilepsy' 3r+ e+' 59,or+% 8iley<Blac>&ellI 2009' p' 6JC<9J' DM4E 6elly 6-/ 2ross )*/ -ac+onal+ )7' Valproic aci+ selectively re+"ces the lo&< threshol+ (:) calci"# c"rrent in rat no+ose ne"rons' 0e"rosci 7ett 1990I116% 233<J' DMCE -acha+o<Vieira )/ 1brahi# 7/ Tarate \r C*' Kistone +eacetylases an+ #oo+ +isor+ers% epi$enetic pro$ra##in$ in $ene<environ#ent interactions' C0S 0e"rosci :her 2011I1M%699<M04' DM6E 2y"lai 7/ Bo&+en C7/ -cElroy S7/ et al' -aintenance e,=cacy o, +ivalproe9 in the prevention o, bipolar +epression' 0e"ropsychophar#acolo$y 2003I2J%13M4<J2' DMME Bon+ \/ 7a# )8/ Zatha# 70' ivalproe9 so+i"# vers"s placebo in the treat#ent o, ac"te bipolar +epression% a syste#atic revie& an+ #eta<analysis' \ *,,ect isor+ 2010I124%22J<34' DMJE Bo&+en C7/ Calabrese \)/ -cElroy S7/ et al' * ran+o#i;e+/ placebo< controlle+ 12<#onth trial o, +ivalproe9 an+ lithi"# in treat#ent o, o"tpatients &ith bipolar 1 +isor+er' ivalproe9 #aintenance st"+y $ro"p' *rch 2en .sychiatry 2000ICM%4J1<9' DM9E 7in+en#ayer \./ 6otsa,tis *' 3se o, so+i"# valproate in violent

an+ a$$ressive behaviors% a critical revie&' \ Clin .sychiatry 2000I61%123<J' DJ0E 7evinson @/ evins>y 5' .sychiatric a+verse events +"rin$ vi$abatrin therapy' 0e"rolo$y 1999IC3%1C03<11'

DJ1E Cha+&ic> ' Sa,ety an+ e,=cacy o, vi$abatrin an+ carba#a;epine in ne&ly +ia$nose+ epilepsy% a #"lticentre ran+o#ise+ +o"ble<blin+ st"+y' Vi$abatrin E"ropean #onotherapy st"+y $ro"p' 7ancet 1999I3C4%13<9' DJ2E @errie C / )obinson )5/ .anayiotopo"los C.' .sychotic an+ severe behavio"ral reactions &ith vi$abatrin% a revie&' *cta 0e"rol Scan+ 1996I93%1<J' DJ3E :ho#as 7/ :ri#ble -/ Sch#it; B/ )in$ K' Vi$abatrin an+ behavio"r +isor+ers% a retrospective s"rvey' Epilepsy )es 1996I2C%21<M' DJ4E 8roe S\' Tonisa#i+e' 1n% Shorvon S/ .er"cca E/ En$el \r \/ e+itors' :he treat#ent o, epilespy' 3r+ e+' 59,or+% 8iley<Blac>&ellI 2009' p' M13<20' DJCE -i#a>i :/ S";">i Z/ :a$a&a :/ 6arasa&a :/ Zab""chi K' D3KE;onisa#i+e bin+in$ in rat brain' -e+ \ 5sa>a 3niv 1990I39%19<22' DJ6E 3e+a Z/ oi :/ :o>"#ar" \/ 8ill#ore 7\' E,,ect o, ;onisa#i+e on #olec"lar re$"< lation o, $l"ta#ate an+ 2*B* transporter proteins +"rin$ epilepto$enesis in rats &ith hippoca#pal sei;"res' Brain )es -ol Brain )es 2003I116%1<6' DJME 5>a+a -/ 6a&ata Z/ -i;"no 6/ 8a+a 6/ 6on+o :/ 6ane>o S' 1nteraction bet&een 2R R Ca / 6 / carba#a;epine an+ ;onisa#i+e on hippoca#pal e9tracell"lar $l"ta#ate #onitore+ &ith a #icro+ialysis electro+e' Br \ .har#acol 199JI124%12MM<JC' DJJE -cElroy S7/ S"ppes :/ 6ec> \r .E/ et al' 5pen<label a+!"nctive ;onisa#i+e in the treat#ent o, bipolar +isor+ers% a prospective trial' \ Clin .sychiatry 200CI66% 61M<24' DJ9E 2hae#i S0/ Shir;a+i **/ 6l"$#an \/ Berv */ .ar+o :B/ @il>o&s>i --' 1s a+!"nctive open<label ;onisa#i+e e,,ective ,or bipolar +isor+erS \ *,,ect isor+ 200JI10C% 311<4' D90E a"phinais / 6nable -/ )osenthal \/ .olans>i -/ )osenthal 0' Tonisa#i+e ,or bipo< lar +isor+er/ #ania or #i9e+ states% a ran+o#i;e+/ +o"ble blin+/ placebo< controlle+ a+!"nctive trial' .sychophar#acol B"ll 2011I44%C1M' D91E 8hite \)/ 8alc;a> :S/ -arino SE/ Benia> :E/ 7eppi> 1E/ Birnba"# *6' Tonisa#i+e +iscontin"ation +"e to psychiatric an+ co$nitive a+verse events% a casecontrol st"+y' 0e"rolo$y 2010IMC%C13<J' D92E -el+r"# BS' 7a#otri$inea novel approach' Sei;"re 1994I3%41<C DS"ppl' *E' D93E C"nnin$ha# -5/ \ones )S' :he anticonv"lsant/ la#otri$ine +ecreases spontaneo"s $l"ta#ate release b"t increases spontaneo"s 2*B* release in the rat entorhinal corte9 in vitro' 0e"rophar#acolo$y 2000I39%2139<46' D94E 8an$ S\/ Sihra :S/ 2ean .8' 7a#otri$ine inhibition o, $l"ta#ate release ,ro# isolate+ cerebrocortical nerve ter#inals (synaptoso#es) by s"ppression o, volta$e<activate+ calci"# channel activity' 0e"roreport 2001I12%22CC<J' D9CE Tona C/ :ancre+i V/ 7on$one ./ et al' 0eocortical potassi"# c"rrents are enhance+ by the antiepileptic +r"$ la#otri$ine' Epilepsia 2002I43%6JC<90' D96E 6oc>i :/ 8ielos; -/ :"rs>i 8*/ 3rbans>a E-' Enhance#ent o, brain >yn"renic aci+ pro+"ction by anticonv"lsantsnovel #echanis# o, antiepileptic activityS E"r \ .har#acol 2006IC41%14M<C1' D9ME @rye -*' Clinical practice' Bipolar +isor+era ,oc"s on +epression' 0 En$l \ -e+ 2011I364%C1<9' D9JE 2oo+&in 2-/ Bo&+en C7/ Calabrese \)/ et al' * poole+ analysis o, 2 placebo< controlle+ 1J<#onth trials o, la#otri$ine an+ lithi"# #aintenance in bipolar 1 +isor+er' \ Clin .sychiatry 2004I6C%432<41' D99E Schin+ler @/ *n$helesc" 12' 7ithi"# vers"s la#otri$ine a"$#entation in treat< #ent resistant "nipolar +epression% a ran+o#i;e+/ open<label st"+y' 1nt Clin .sychophar#acol 200MI22%1M9<J2' D100E Ettin$er *B/ 6"stra )./ Ka##er *E' E,,ect o, la#otri$ine on +epressive sy#p< to#s in a+"lt patients &ith epilepsy' Epilepsy Behav 200MI10%14J<C4' D101E 6re#er 1/ Vass */ 2oreli> 1/ et al' .lacebo<controlle+ trial o, la#otri$ine a++e+ to conventional an+ atypical antipsychotics in schi;ophrenia' Biol .sychiatry 2004IC6%441<6' D102E 2o,, C/ 6ee,e )/ Citro#e 7/ et al' 7a#otri$ine as a++<on therapy in schi;ophre< nia% res"lts o, 2 placebo<controlle+ trials' \ Clin .sychophar#acol 200MI2M% CJ2<9' D103E :ritt 6/ 0ic>el C/ 7ah#ann C/ et al' 7a#otri$ine treat#ent o, a$$ression in ,e#ale bor+erline<patients% a ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+ st"+y' \ .sychophar#acol 200CI19%2JM<91' D104E )eich B/ Tanarini -C/ Bieri 6*' * preli#inary st"+y o, la#otri$ine in the treat#ent o, a,,ective instability in bor+erline personality +isor+er' 1nt Clin .sychophar#acol 2009I24%2M0<C' D10CE Beran )2/ 2ibson )\' *$$ressive behavio"r in intellect"ally challen$e+ patients &ith epilepsy treate+ &ith la#otri$ine' Epilepsia 199JI39%2J0<2' D106E Besa$ @-' Behavio"ral e,,ects o, the ne&er antiepileptic +r"$s% an "p+ate' E9pert 5pin r"$ Sa, 2004I3%1<J' D10ME -cCabe ):/ 8asterlain C2/ 6"charc;y> 0/ So=a ) / Vo$el \)' Evi+ence ,or anticonv"l< sant an+ ne"roprotectant action o, ,elba#ate #e+iate+ by strychnine<insensitive $lycine receptors' \ .har#acol E9p :her 1993I264%124J<C2' D10JE 6etter :*/ .ost )-/ :heo+ore 8K' .ositive an+ ne$ative psychiatric e,,ects o, antiepileptic +r"$s in patients &ith sei;"re +isor+ers' 0e"rolo$y 1999IC3(C S"ppl 2)%SC3<6M' D109E 2ay .E/ -echa# 2@/ Cos>ey \S/ Sa+ler :/ :ho#pson \*' Behavioral e,,ects o, ,elba#ate in chil+hoo+ epileptic encephalopathy (7enno92asta"t syn+ro#e)' .sychol )ep 199CIMM(3 .t 2)%120J<10' D110E :heo+ore 8K/ *lbert ./ Stert; B/ et al' @elba#ate #onotherapy% i#plications ,or antiepileptic +r"$ +evelop#ent' Epilepsia 199CI36%110C<10' D111E .an+e *C/ avi+son \)/ \e,,erson \8/ et al' :reat#ent o, social phobia &ith $abapentin% a placebo<controlle+ st"+y' \ Clin .sychophar#acol 1999I19%341<J' D112E .an+e *C/ Croc>att \2/ \anney C*/ 8erth \7/ :saro"cha 2' 2abapentin in bipolar +isor+er% a placebo<controlle+ trial o, a+!"nctive therapy' 2abapentin bipolar +isor+er st"+y $ro"p' Bipolar isor+ 2000I2(3 .t 2)%249<CC' D113E @rye -*/ 6etter :*/ 6i#brell :*/ et al' * placebo<controlle+ st"+y o, la#otri$ine an+ $abapentin #onotherapy in re,ractory #oo+ +isor+ers' \ Clin .sychophar#acol 2000I20%60M<14'

D114E Vieta E/ -an"el 2oi>olea \/ -artine;<*ran */ et al' * +o"ble<blin+/ ran+o#i;e+/ placebo<controlle+/ prophyla9is st"+y o, a+!"nctive $abapentin ,or bipolar +isor+er' \ Clin .sychiatry 2006I6M%4M3<M' D11CE 8ol, S-/ Shinnar S/ 6an$ K/ 2il 6B/ -oshe S7' 2abapentin to9icity in chil+ren #ani,estin$ as behavioral chan$es' Epilepsia 199CI36%1203<C' D116E 7ee 5/ Stein$ar+ )\/ Cesena -/ Kel#ers S7/ )iviello \\/ -i>ati -*' Behavioral si+e e,,ects o, $abapentin in chil+ren' Epilepsia 1996I3M%JM<90' D11ME -"la -/ :ri#ble -)/ 7hatoo S / San+er \8' :opira#ate an+ psychiatric a+verse events in patients &ith epilepsy' Epilepsia 2003I44%6C9<63' D11JE -"la -/ Kes+or,,er C/ :ri#ble -/ San+er \8' :he role o, titration sche+"le o, topira#ate ,or the +evelop#ent o, +epression in patients &ith epilepsy' Epilepsia 2009IC0%10M2<6' D119E 0ic>el C/ 7ah#ann C/ :ritt 6/ et al' :opira#ate in treat#ent o, +epressive an+ an$er sy#pto#s in ,e#ale +epressive patients% a ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+ st"+y' \ *,,ect isor+ 200CIJM%243<C2' D120E -o&la */ 6ar+eh E' :opira#ate a"$#entation in patients &ith resistant #a!or +epressive +isor+er% a +o"ble<blin+ placebo<controlle+ clinical trial' .ro$ 0e"ropsychophar#acol Biol .sychiatry 2011I3C%9M0<3' D121E 0ic>el -6/ 0ic>el C/ -itterlehner @5/ et al' :opira#ate treat#ent o, a$$ression in ,e#ale bor+erline personality +isor+er patients% a +o"ble<blin+/ placebo< controlle+ st"+y' \ Clin .sychiatry 2004I6C%1C1C<9' D122E 0ic>el -6/ 0ic>el C/ 6aplan ./ et al' :reat#ent o, a$$ression &ith topira#ate in #ale bor+erline patients% a +o"ble<blin+/ placebo<controlle+ st"+y' Biol .sychiatry 200CICM%49C<9' D123E :iihonen \/ Kalonen ./ 8ahlbec> 6/ et al' :opira#ate a++<on in treat#ent< resistant schi;ophrenia% a ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+/ cross< over trial' \ Clin .sychiatry 200CI66%1012<C' D124E *,shar K/ )ooha,;a K/ -o"savi 2/ et al' :opira#ate a++<on treat#ent in schi;ophrenia% a ran+o#ise+/ +o"ble<blin+/ placebo<controlle+ clinical trial' \ .sychophar#acol 2009I23%1CM<62' D12CE -"scatello -)/ Br"no */ .an+ol,o 2/ et al' :opira#ate a"$#entation o, clo;apine in schi;ophrenia% a +o"ble<blin+/ placebo<controlle+ st"+y' \ .sychophar#acol 2011I2C%66M<M4' D126E elbello -./ @in+lin$ )7/ 6"shner S/ et al' * pilot controlle+ trial o, topira#ate ,or #ania in chil+ren an+ a+olescents &ith bipolar +isor+er' \ *# *ca+ Chil+ *+olesc .sychiatry 200CI44%C39<4M' D12ME )oy Chen$appa 60/ Sch&ar;#an 76/ K"lihan \@/ Vian$ \/ )osenthal 0)' *+!"nc< tive topira#ate therapy in patients receivin$ a #oo+ stabili;er ,or bipolar 1 +isor+er% a ran+o#i;e+/ placebo<controlle+ trial' \ Clin .sychiatry 2006I6M% 169J<M06' D12JE 7in+ley SE/ Carlson EB/ Kill 6' * ran+o#i;e+/ +o"ble<blin+/ placebo<controlle+ trial o, a"$#entation topira#ate ,or chronic co#bat<relate+ posttra"#atic stress +isor+er' \ Clin .sychophar#acol 200MI2M%6MM<J1' D129E :"c>er ./ :ra"t#an )./ 8yatt B/ et al' E,=cacy an+ sa,ety o, topira#ate #onotherapy in civilian posttra"#atic stress +isor+er% a ran+o#i;e+/ +o"ble< blin+/ placebo<controlle+ st"+y' \ Clin .sychiatry 200MI6J%201<6' D130E 7eo#br"ni ./ 7ava$nino 7/ @assino S' :reat#ent o, obese patients &ith bin$e eatin$ +isor+er "sin$ topira#ate% a revie&' 0e"ropsychiatr is :reat 2009IC% 3JC<92' D131E -"la -/ Cavanna *E/ -onaco @' .sychophar#acolo$y o, topira#ate% ,ro# epilepsy to bipolar +isor+er' 0e"ropsychiatr is :reat 2006I2%4MC<JJ' D132E o+rill CB/ *rnett \7/ Sh" V/ .i9ton 2C/ 7en; 2:/ So##erville 68' E,,ects o, tia$abine #onotherapy on abilities/ a+!"st#ent/ an+ #oo+' Epilepsia 199JI39%33< 42' D133E S"ppes :/ Chishol# 6*/ havale / et al' :ia$abine in treat#ent re,ractory bipo< lar +isor+er% a clinical case series' Bipolar isor+ 2002I4%2J3<9' D134E )osenthal -' :ia$abine ,or the treat#ent o, $enerali;e+ an9iety +isor+er% a ran+o#i;e+/ open<label/ clinical trial &ith paro9etine as a positive control' \ Clin .sychiatry 2003I64%124C<9' D13CE 7eppi> 1E' :ia$abine% the sa,ety lan+scape' Epilepsia 199CI36(S"ppl' 6)%S10<3' D136E 8a$ner 6 / 6o&atch )*/ E#slie 2\/ et al' * +o"ble<blin+/ ran+o#i;e+/ placebo<controlle+ trial o, o9carba;epine in the treat#ent o, bipolar +isor+er in chil+ren an+ a+olescents' *# \ .sychiatry 2006I163%11M9<J6' D13ME Vas"+ev */ -acritchie 6/ Vas"+ev 6/ 8atson S/ 2e++es \/ Zo"n$ *K' 59carba;epine ,or ac"te a,,ective episo+es in bipolar +isor+er' Cochrane atabase Syst )ev 2011% C 004JCM' D13JE Vas"+ev */ -acritchie 6/ 8atson S/ 2e++es \)/ Zo"n$ *K' 59carba;epine in the #ain< tenance treat#ent o, bipolar +isor+er' Cochrane atabase Syst )ev 200J%C 00C1M1' D139E -attes \*' 59carba;epine in patients &ith i#p"lsive a$$ression% a +o"ble<blin+/ placebo<controlle+ trial' \ Clin .sychophar#acol 200CI2C%CMC<9' D140E -"la -/ -onaco @' *ntiepileptic +r"$s an+ psychopatholo$y o, epilepsy% an "p+ate' Epileptic isor+ 2009I11%1<9' D141E 7ynch B*/ 7a#ben$ 0/ 0oc>a 6/ et al' :he synaptic vesicle protein SV2* is the bin+in$ site ,or the antiepileptic +r"$ levetiraceta#' .roc 0atl *ca+ Sci 3 S * 2004I101%9J61<6' D142E @rench \*/ :onner @' 7evetiraceta#' 1n% Shorvon S/ .er"cca E/ En$el \r \/ e+itors' :he treat#ent o, epilepsy' 3r+ e+' 59,or+% 8iley<Blac>&ellI 2009' p' CC9<M4' D143E -"rali+haran */ Bha$&a$ar T' .otential o, levetiraceta# in #oo+ +isor+ers% a preli#inary revie&' C0S r"$s 2006I20%969<M9' D144E Than$ 8/ Connor 6-/ avi+son \)' 7evetiraceta# in social phobia% a placebo controlle+ pilot st"+y' \ .sychophar#acol 200CI19%CC1<3' D14CE Saricice> */ -aloney 6/ -"rali+haran */ et al' 7evetiraceta# in the #ana$e#ent o, bipolar +epression% a ran+o#i;e+/ +o"ble<blin+/ placebo< controlle+ trial' \ Clin .sychiatry 2011IM2%M44<C0' D146E Stein -B/ )avin+ran 70/ Si#on 0-/ et al' 7evetiraceta# in $enerali;e+ social an9iety +isor+er% a +o"ble<blin+/ ran+o#i;e+ controlle+ trial' \ Clin .sychiatry 2010IM1%62M<31'

D14ME -attes \*' 7evetiraceta# in patients &ith i#p"lsive a$$ression% a +o"ble<blin+/ placebo<controlle+ trial' \ Clin .sychiatry 200JI69%310<C' D14JE -"la -/ :ri#ble -)/ Z"en */ 7i" )S/ San+er \8' .sychiatric a+verse events +"rin$ levetiraceta# therapy' 0e"rolo$y 2003I61%M04<6' D149E 8hite \)/ 8alc;a> :S/ 7eppi> 1E/ et al' iscontin"ation o, levetiraceta# beca"se o, behavioral si+e e,,ects% a casecontrol st"+y' 0e"rolo$y 2003I61% 121J<21' D1C0E Kel#stae+ter C/ -ihov Z/ :oliat -)/ et al' 2enetic variation in +opa#iner$ic activity is associate+ &ith the ris> ,or psychiatric si+e e,,ects o, levetiraceta#' Epilepsia (in press)' D1C1E 6assai B/ Chiron C/ *"$ier S/ et al' Severe #yoclonic epilepsy in in,ancy% a syste#atic revie& an+ a #eta<analysis o, in+ivi+"al patient +ata' Epilepsia 200JI49%343<J' D1C2E @isher \7' :he e,,ects o, stiripentol on 2*B*(*) receptors' Epilepsia 2011IC2(S"ppl' 2)% M6<J' D1C3E Chiron C/ -archan+ -C/ :ran */ et al' Stiripentol in severe #yoclonic epilepsy in in,ancy% a ran+o#ise+ placebo<controlle+ syn+ro#e<+e+icate+ trial' S:1C75 st"+y $ro"p' 7ancet 2000I3C6%163J<42' D1C4E 1no"e Z/ 5hts">a Z/ 5$"ni K/ et al' Stiripentol open st"+y in \apanese patients &ith ravet syn+ro#e' Epilepsia 2009IC0%2362<J' D1CCE -ont$o#ery S/ Chata#ra 6/ .a"er 7/ 8halen E/ Bal+inetti @' E,=cacy an+ sa,ety o, pre$abalin in el+erly people &ith $eneralise+ an9iety +isor+er' Br \ .sychiatry 200JI193%3J9<94' D1C6E 6asper S/ Ker#an B/ 0ivoli 2/ et al' E,=cacy o, pre$abalin an+ venla,a9ine<V) in $enerali;e+ an9iety +isor+er% res"lts o, a +o"ble<blin+/ placebo<controlle+ J<&ee> trial' 1nt Clin .sychophar#acol 2009I24%JM<96' D1CME @eltner E/ 7i"< "#a& -/ Sch&ei;er E/ Biels>i )' E,=cacy o, pre$abalin in $ener< ali;e+ social an9iety +isor+er% res"lts o, a +o"ble<blin+/ placebo<controlle+/ =9e+<+ose st"+y' 1nt Clin .sychophar#acol 2011I26%213<20' D1CJE 2reist \K/ 7i"< "#a& -/ Sch&ei;er E/ @eltner ' E,=cacy o, pre$abalin in preventin$ relapse in patients &ith $enerali;e+ social an9iety +isor+er% res"lts o, a +o"ble<blin+/ placebo<controlle+ 26<&ee> st"+y' 1nt Clin .sychophar#acol 2011I26%243<C1' D1C9E En$lisch S/ Esser */ Ennin$ @/ Koh#ann S/ Schan; K/ Tin> -' *"$#entation &ith pre$abalin in schi;ophrenia' \ Clin .sychophar#acol 2010I30%43M<40' D160E Sho&ra>i -' .re$abalin in the treat#ent o, +epression' \ .sychophar#acol 200MI21%JJ3<4' D161E Taccara 2/ 2an$e#i ./ .er"cca ./ Specchio 7' :he a+verse event pro=le o, pre$abalin% a syste#atic revie& an+ #eta<analysis o, ran+o#i;e+ controlle+ trials' Epilepsia 2011IC2%J26<36' D162E Z"en *8/ Sin$h )/ Bell 2S/ et al' :he lon$<ter# retention o, pre$abalin in a lar$e cohort o, patients &ith epilepsy at a tertiary re,erral centre' Epilepsy )es 2009IJM%120<3' D163E *rroyo S' )"=na#i+e' 0e"rotherape"tics 200MI4%1CC<62' D164E 8heless \8/ Conry \/ 6ra"ss 2/ -ann */ 7o.resti */ 0ar"r>ar -' Sa,ety an+ tolerability o, r"=na#i+e in chil+ren &ith epilepsy% a poole+ analysis o, M clini< cal st"+ies' \ Chil+ 0e"rol 2009I24%1C20<C' D16CE @ava -' :he possible antian9iety an+ #oo+<stabili;in$ e,,ects o, r"=na#i+e' .sychother .sychoso# 2010IM9%194<C' D166E 6a",#an 6)/ Str"c> .\' *ctivation o, s"ici+al i+eation &ith a+!"nctive r"=na#i+e in bipolar +isor+er' Epilepsy Behav 2010I20%3J6<9' D16ME @attore C/ .er"cca E' 0ovel #e+ications ,or epilepsy' r"$s 2011IM1%21C1<MJ' D16JE Errin$ton *C/ Stohr :/ Keers C/ 7ees 2' :he investi$ational anticonv"lsant lacosa#i+e selectively enhances slo& inactivation o, volta$e<$ate+ so+i"# channels' -ol .har#acol 200JIM3%1CM<69' D169E Becerra \7/ 5!e+a \/ Corre+era E/ )"i; 2i#ene; \' )evie& o, therape"tic options ,or a+!"vant treat#ent o, ,ocal sei;"res in epilepsy% ,oc"s on lacosa#i+e' C0S r"$s 2011I2C(S"ppl' 1)%316' D1M0E Kain;l / .ara+a */ Soares<+a<Silva .' -etabolis# o, t&o ne& antiepileptic +r"$s an+ their principal #etabolites S(R)< an+ )(`)<10/11<+ihy+ro<10< hy+ro9y carba#a;epine' Epilepsy )es 2001I44%19M<206' D1M1E 2"nthorpe -\/ 7ar$e CK/ San>ar )' :he #echanis# o, action o, reti$abine (e;o$abine)/ a =rst<in<class 6 R channel opener ,or the treat#ent o, epilepsy' Epilepsia 2012IC3%412<24' D1M2E enc>er / K"s"# K' *nti#anic e,=cacy o, reti$abine in a propose+ #o"se #o+el o, bipolar +isor+er' Behav Brain )es 2010I20M%MJ<J3' D1M3E 6ors$aar+ -./ Kart; B./ Bro&n 8 / *hrin$ .6/ Strobae> / -ir;a 0)' *n9iolytic e,,ects o, -a9ipost (B-S<2043C2) an+ reti$abine via activation o, ne"ronal 6vM channels' \ .har#acol E9p :her 200CI314%2J2<92' D1M4E .orter )\/ .artiot */ Sach+eo )/ 0ohria V/ *lves 8-' )an+o#i;e+/ #"lticenter/ +ose<ran$in$ trial o, reti$abine ,or partial<onset sei;"res' 0e"rolo$y 200MI6J% 119M<204' D1MCE Bro+ie -\/ 7erche K/ 2il<0a$el */ et al' E,=cacy an+ sa,ety o, a+!"nctive e;o$abine (reti$abine) in re,ractory partial epilepsy' 0e"rolo$y 2010IMC%1J1M<24' D1M6E @rench \*/ *bo"<6halil B8/ 7eroy )@/ et al' )an+o#i;e+/ +o"ble<blin+/ placebo< controlle+ trial o, e;o$abine (reti$abine) in partial epilepsy' 0e"rolo$y 2011IM6% 1CCC<63' D1MME .oti$a' .recribin$ in,or#ation' )esearch :rian$le .ar> (0C)% 2la9oS#ith6lineI 2012 DonlineE' *vailable ,ro# 3)7% http%((&&&'access+ata',+a'$ov(+r"$sat,+aa +ocs(label(2011(02234Cs000lbl'p+, ' D*ccesse+ 29 \"ne 2012E' D1MJE .er"cca ./ 2illia# @2' *+verse e,,ects o, antiepileptic +r"$s' 7ancet 0e"rol 2012I11%M92<J02' D1M9E -arson *2/ 8illia#son .)' 1nterpretin$ re$"latory trials in epilepsy' C"rr 5pin 0e"rol 2009I22%16M<M3' D1J0E Ko&ar+ ./ :&ycross )/ Sh"ster \/ -ihalyo -/ )e#i \/ 8ilcoc> *' *nti<epileptic +r"$s' \ .ain Sy#pto# -ana$e 2011I42%MJJ<J04'