Pharmacotherapy_for_anxiety_disorders

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P harm aco th era p y f o r a n xie ty d is o rd ers in c h ild re n a n d a d ole scen ts
A uth ors : K im berly G la zie r L eonte , P hD , A nth ony P ulia fic o , P hD , P ete r N a, M D , M oir a A R yn n, M D
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All to pic s a re u pdate d a s n ew e vid ence b eco m es a va ila ble a nd o ur p eer r e vie w p ro ce ss is
c o m ple te .
L it e ra tu re r e vie w c u rre n t t h ro ugh: J a n 2 018. | T his t o pic la st u pdate d : J u n 2 2, 2 017.
IN TR O DUCTIO N — Anxie ty d is ord ers a re th e m ost c o m mon p sych ia tr ic d is ord ers d ia gnose d in
c h ild hood a nd a dole sce nce [ 1 ,2 ]. A nxie ty d is ord ers th at m ay b egin in c h ild hood in clu de
genera liz ed a nxie ty d is ord er, s o cia l a nxie ty d is ord er, s e le ctiv e m utis m , p anic d is ord er,
a gora phobia , s e para tio n a nxie ty d is ord e r, a nd s p ecific p hobia .
Pedia tr ic a nxie ty d is ord ers a re a sso cia te d w ith in cre ase d d iffic ulty in s ch ool p erfo rm ance a nd
peer r e la tio nsh ip s [ 3 -5 ]. W hen le ft u ntr e ate d, a nxie ty d is ord ers s ta rtin g in c h ild hood te nd to
p ers is t in to a dulth ood, a nd a re fr e quently a sso cia te d w ith d epre ssio n [ 6], s u bsta nce a buse
[7 ,8 ], o ccu patio nal im pairm ent [ 9], a nd s u ic id al b ehavio r [ 1 0 ].
P harm aco th era py fo r a nxie ty d is ord ers in c h ild re n w ill be d is cu sse d h ere . T he e pid em iology,
p ath ogenesis , c lin ical m anife sta tio ns, c o urs e , a nd d ia gnosis o f a nxie ty d is ord ers in c h ild re n a re
d is cu sse d s e para te ly . P sych oth era py fo r a nxie ty d is ord ers in c h ild re n is a ls o d is cu sse d
se para te ly . O bse ssiv e c o m puls ive d is ord e r a nd p osttr a um atic s tr e ss d is ord er in c h ild re n a nd
adole sce nts a re a ls o d is cu sse d s e para te ly . ( S ee "A nxie ty d is ord ers in c h ild re n a nd a dole sce nts :
E pid em iology, p ath ogenesis , c lin ical m anife sta tio ns, a nd c o urs e " a nd "O ve rv ie w o f fe ars a nd
phobia s in c h ild re n a nd a dole sce nts " a nd "P sych oth era py fo r a nxie ty d is ord ers in c h ild re n a nd
adole sce nts " a nd "O bse ssiv e-c o m puls ive d is ord er in c h ild re n a nd a dole sce nts : E pid em iology,
p ath ogenesis , c lin ical m anife sta tio ns, c o urs e , a sse ssm ent, a nd d ia gnosis " a nd "T re atm ent o f
obse ssiv e-c o m puls ive d is ord er in c h ild re n a nd a dole sce nts " a nd "P sych oso cia l in te rv e ntio ns fo r
posttr a um atic s tr e ss d is ord er in c h ild re n a n d a dole sce nts " .)
A NTID EPR ESSA NTS — For m ost c h ild re n r e ce iv in g m edic atio n tr e atm ent fo r a n a nxie ty
d is ord er, w e s u ggest fir st- lin e tr e atm ent w ith a s e le ctiv e s e ro to nin r e upta ke in hib ito r ( S SR I) ,
r a th er th an o th er tr e atm ents . S ero to nin -n ore pin ephrin e r e upta ke in hib ito rs ( S N RIs ) a nd tr ic yclic
a ntid epre ssa nts h ave a ls o s h ow n e ff ic acy in th e tr e atm ent o f p edia tr ic a nxie ty d is ord ers .
B eca use th ey a re a sso cia te d w ith le ss e asily to le ra te d s id e e ff e cts c o m pare d w ith S SR Is , th ese
d ru gs a re g enera lly u se d s e co nd- o r th ird -lin e.
®

SSR I/S N RI — Sero to nin r e upta ke in hib ito rs ( S R Is ) u se d in th e tr e atm ent o f p edia tr ic a nxie ty
d is ord ers in clu de S SR Is , S N RIs , a nd clo m ipra m ine . ( S ee 'T ric yclic a ntid epre ssa nts ' b elo w.)
E ffic acy — SSR Is a nd S N RIs , a s a c la ss, a re c o nsid ere d e ff e ctiv e fo r p edia tr ic a nxie ty
d is ord ers A m eta -a naly sis o f 1 6 r a ndom ized tr ia ls o n p ublis hed b etw een 1 992 a nd 2 008 fo und
a n um ber o f S SR I a nd S N RI m edic atio ns – flu oxe tin e , s e rtr a lin e , flu vo xa m ine , p aro xe tin e , a nd
ve nla fa xin e – to b e s u perio r to p la ce bo in th e tr e atm ent o f p edia tr ic a nxie ty [ 1 1 ,1 2 ]. A m ong th e
S N RIs c lin ical tr ia ls s u ggest th at v e nla fa xin e S R , in p artic ula r, is e ff e ctiv e fo r th ese d is ord ers . A
2 015 tr ia l su ggeste d th at d ulo xe tin e m ay b enefit y o uth w ith G AD [ 1 3 ]. S om e c h ild re n
exp erie nce d w eig ht lo ss, in cre ase d c h ole ste ro l, a nd c h anges in v ita l sig ns w hile ta kin g th e
m edic atio n.
G en era liz e d a n xie ty d is o rd er — Tw o r a ndom ized tr ia ls b y th e s a m e r e se a rc h te am
fo und th at th e S N RI v e nla fa xin e a nd th e S SR I s e rtr a lin e r e duce d s ym pto m s o f g enera liz ed
anxie ty d is ord er ( G AD ) in c h ild re n a nd a dole sce nts d ia gnose d w ith th e d is ord er:
S ocia l a n xie ty d is o rd er — Random ized tr ia ls h ave fo und th e S N RI v e nla fa xin e a nd th e
S SR Is flu oxe tin e a nd paro xe tin e r e duce d s ym pto m s o f D SM -IV s o cia l p hob ia ( re nam ed s o cia l
anxie ty d is ord er in D SM -5 ) in c h ild re n a nd a dole sce nts .
A n e ig ht- w eek r a ndom ized tr ia l o f 3 20 y o u th s ( a ges 6 to 1 7) w ith G AD fo und ve nla fa xin e
exte nded r e le ase ( E R ) to b e s u perio r to p la ce bo in r e ductio n o f G AD s ym pto m s a nd in th e
pro portio n o f p atie nts r e sp ondin g to tr e atm ent ( 6 9 v e rs u s 4 8 p erc e nt) [ 1 4 ].

A n in e-w eek tr ia l ra ndom ly a ssig ned 2 2 p a rtic ip ants ( a ges 5 to 1 7) w ith G AD to e ith er
se rtr a lin e o r p la ce bo. T re atm ent w ith s e rtr a lin e le d to g re ate r s ym pto m r e ductio n c o m pare d
w ith p la ce bo a cco rd in g to th e H am ilton A nxie ty R atin g S ca le . D izzin ess ( 6 4 v e rs u s 1 8
perc e nt) a nd n ause a ( 5 5 v e rs u s 5 p erc e n t) w ere m ore c o m monly e xp erie nce d b y
partic ip ants ta kin g s e rtr a lin e c o m pare d w ith p la ce bo; h ow eve r, th ese d iffe re nce s w ere n ot
sta tis tic ally s ig nific ant in th is s m all sa m ple [ 1 2 ].

A 1 0-w eek r a ndom ized tr ia l a ssig ned 2 72 y o uth ( a ges 7 to 1 7) w ith G AD to dulo xe tin e o r
pla ce bo. D ulo xe tin e w as a sso cia te d w ith g re ate r s ym pto m r e ductio n o n th e P edia tr ic
A nxie ty R atin g S ca le , r e m issio n a nd fu nctio nal im pro ve m ent c o m pare d w ith p la ce bo.
D ulo xe tin e w as a ls o a sso cia te d w ith w eig ht lo ss a nd c h anges in p uls e a nd b lo od p re ssu re
[1 3 ].

A 1 6-w eek r a ndom ized tr ia l o f 3 22 p artic ip ants ( a ges 8 to 1 7) w ith s o cia l p hobia c o m pare d
tr e atm ent w ith paro xe tin e w ith p la ce bo [ 1 5 ]. P aro xe tin e le d to a h ig her r e sp onse r a te th an
pla ce bo ( 7 8 v e rs u s 3 8 p erc e nt) .

A 1 6-w eek tr ia l ra ndom ly a ssig ned 2 93 y o uth s w ith s o cia l a nxie ty d is ord er ( a ges 8 to 1 7) to
v e nla fa xin e E R o r p la ce bo [ 1 6 ]. V enla fa xin e le d to a h ig her r e sp onse r a te c o m pare d w ith
p la ce bo ( 5 6 v e rs u s 3 7 p erc e nt) .

A 1 2-w eek c lin ical tr ia l ra ndom ly a ssig ne d 1 22 in div id uals w ith s o cia l p hobia ( a ges 7 to 1 7)
to flu oxe tin e , b ehavio ra l tr e atm ent o r p la ce bo [ 1 7 ]. A t th e e nd o f th e tr e atm ent p erio d, th e
pro portio n o f p atie nts n o lo nger m eetin g c rit e ria fo r s o cia l p hobia w ere m uch g re ate r fo r


Sele ctiv e m utis m — Very s m all ra ndom ized tr ia ls o f a n S SR I in ch ild re n/a dole sce nts
w ith s e le ctiv e m utis m ( w ith a nd w ith out c o -o ccu rrin g a nxie ty d is ord ers ) fo und n o d iffe re nce
b etw een g ro ups tr e ate d w ith a n S SR I v e rs u s p la ce bo. A s m all but s lig htly la rg er u nco ntr o lle d
tr ia l h ad m ore p ro m isin g r e su lts.
P an ic d is o rd er — Thre e u nco ntr o lle d tr ia ls w ith a to ta l o f 4 6 p edia tr ic s u bje cts w ith p anic
dis ord er tr e ate d w ith a n S SR I e xp erie nce d r e sp onse r a te s b etw een 7 5 a nd 9 0 p erc e nt [ 2 1-2 3 ].
S pecif ic p hobia s — An u nco ntr o lle d tr ia l te ste d flu oxe tin e in s ix y o uth s ( a ges 1 0 to 1 7)
w ho m et c rit e ria fo r s p ecific p hobia a nd a t le ast o ne a dditio nal a nxie ty d is ord er [ 2 4 ]. T hre e o f
six w ere r a te d a s “ im pro ve d” a nd tw o w ere r a te d a s “ m uch im pro ve d” a fte r n in e w eeks o f
tr e atm ent [ 2 3 ].
O th er — Thre e r a ndom ized tr ia ls c o m pare d S SR Is w ith p la ce bo in a to ta l o f 7 06 y o uth
w ith a m ix o f a nxie ty d is ord ers ( G AD , s e para tio n a nxie ty d is ord er, o r s o cia l p hobia ). R esp onse
ra te s r a nged fr o m 5 4.9 to 7 6 p erc e nt o f th e m ixed s a m ple s a fte r 8 to 1 2 w eeks o f tr e atm ent [ 2 5-
27 ]. A tr ia l th at r e porte d r e su lts b y d is ord er fo und im pro ve m ent in r e sp onse to a n S SR I in
s u bje cts w ith s o cia l p hobia a nd g enera liz ed a nxie ty d is ord er c o m pare d w ith p la ce bo, b ut n ot
w ith s e para tio n a nxie ty d is ord er [ 2 7 ].
T here h ave b een n o c lin ical tr ia ls o f S R Is in c h ild re n w ith a gora phobia o r s e para tio n a nxie ty
d is ord er a lo ne.
A dvers e e ffe cts — The r is ks a sso cia te d w ith S SR Is /S N RIs fo r p edia tr ic a nxie ty s h ould b e
ca re fu lly w eig hed a gain st th eir p ote ntia l b enefit s w heneve r th e u se o f th ese m edic atio ns is
c o nsid ere d. R isks a nd b enefit s s h ould b e d is cu sse d w ith b oth th e p are nts a nd c h ild b efo re
in itia tin g tr e atm ent. S SR Is h ave b een a ss o cia te d w ith p sych ia tr ic a dve rs e e ve nts , s u ch a s
dis in hib itio n, a gita tio n, a nd w ors e nin g o f a nxie ty s ym pto m s. P hysic al sid e e ff e cts m ost
co m monly in clu de h eadach es, g astr ic d is tr e ss, a nd s le ep d is tu rb ance [ 2 8 ]. A ntid epre ssa nt
behavio ra l tr e atm ent a nd flu oxe tin e c o m pare d w ith p la ce bo ( 5 3 a nd 2 1.2 v e rs u s 3 .1
p erc e nt) .
A 1 2-w eek c lin ical tr ia l ra ndom ly a ssig ne d 1 5 y o uth s to e ith er flu oxe tin e o r p la ce bo [ 1 8 ]. N o
diffe re nce s b etw een g ro ups w ere fo und b etw een g ro ups b ase d o n c lin icia n a nd te ach er
ra tin gs; p are nt r a tin gs fo und p artic ip ants a ssig ned to flu oxe tin e im pro ve d c o m pare d w ith
th ose in th e p la ce bo g ro up. S ym pto m r e ductio n w as s e en b oth g ro ups; h ow eve r,
p artic ip ants r e m ain ed h ig hly s ym pto m atic .

A 1 6-w eek c lin ical tr ia l o f fiv e c h ild re n ( a ge d 5 to 1 1 y e ars ) w ith s e le ctiv e m utis m s h ow ed
no d iffe re nce in s ym pto m c h ange b etw een se rtr a lin e a nd p la ce bo-tr e ate d g ro ups [ 1 9 ].

A n in e-w eek, u nco ntr o lle d tr ia l o f flu oxe tin e in 2 1 y o uth s a ges 5 to 1 4 w ith s e le ctiv e m utis m
alo ng w ith a c o ncu rre nt D SM -IIIR a nxie ty d is ord er ( s e para tio n a nxie ty d is ord er,
o ve ra nxio us d is ord er/G AD , a vo id ant d is ord er, o r s o cia l p hobia ) fo und 7 6 p erc e nt o f th e
sa m ple to e xp erie nce im pro ve d s ym pto m s, w ith d im inished a nxie ty a nd in cre ase d s p eech
[2 0 ].


medic atio ns a re a sso cia te d w ith a n in cre ase d r is k o f s u ic id alit y in c h ild re n, w hic h w e a ddre ss
b elo w. ( S ee 'S uic id alit y a nd a ntid epre ssa nts in c h ild re n' b elo w.)
S om e c h ild re n r e ce iv in g ve nla fa xin e h ave b een r e porte d to e xp erie nce w eig ht g ain , e le va te d
ch ole ste ro l, a nd h yp erte nsio n.
A dm in is tr a tio n — SR Is a re g enera lly s ta rte d a t th e lo west a va ila ble d ose in c h ild re n. A fte r
a w eek d urin g w hic h th e p atie nt is k n ow n t o b e ta kin g th e m edic atio n a nd to le ra tin g it w ith
m inim al sid e e ff e cts , th e d ose c a n b e in cre ase d in cre m enta lly to a n in itia l th era peutic d ose . If
s ym pto m s d o n ot r e m it a fte r s ix to e ig ht w eeks, th e d ose is in cre ase d in cre m enta lly a nd te ste d,
until th e m axim um d ose is r e ach ed o r s id e e ff e cts a re n ot to le ra ble . A ntid epre ssa nts o fte n
re quire d osa ges s im ilar to th ose in a dults , d ue to th e fa st m eta bolis m s e en in c h ild re n. A ta ble
su m mariz es in itia l d aily d ose s, th era peutic r a nges, a nd s u ggeste d d ose tit ra tio n r a te s fo r S SR Is
in a nxie ty d is ord ers in c h ild re n ( ta ble 1 ) .
A s a n e xa m ple , s e rtr a lin e c a n b e s ta rte d a t a n in itia l d ose o f 1 2.5 to 2 5 m g/d ay fo r a m inim um
of s e ve n d ays a nd tit ra te d u p to 5 0 m g/d ay in in cre m ents o f 1 2.5 m g ( c h ild ) o r 2 5 to 5 0 m g
(a dole sce nt) p er w eek. If a n a dequate c lin ical re sp onse is n ot s e en a fte r s ix to e ig ht w eeks o f
tr e atm ent, s u bse quent tr ia ls s h ould b e tr ie d fo llo win g d ose in cre ase s o f 1 2.5 m g/d ay fo r
ch ild re n a nd 2 5 to 5 0 m g/d ay fo r a dole sce nts to a m axim um o f 2 00 m g/d ay .
W hen s to ppin g a n S SR I, d ecre ase th e d ose g ra dually to a vo id d is co ntin uatio n s ym pto m s, e g,
by 2 5 to 5 0 p erc e nt w eekly . D urin g th e ta perin g p erio d, th e tr e atin g c lin icia n s h ould c a re fu lly
m onito r th e c h ild o r a dole sce nt fo r a dve rs e e ve nts .
F ollo win g r e ports o f a sso cia tio ns b etw een a ntid epre ssa nt u se a nd s u ic id alit y in c h ild re n, th e U S
Food a nd D ru g A dm inistr a tio n ( F D A) m ad e r e co m mendatio ns r e gard in g c lin ical m onito rin g a nd
dura tio n o f th e m edic atio ns, b elo w. ( S ee 'S uic id alit y a nd a ntid epre ssa nts in c h ild re n' b elo w.)
A ugm en ta tio n — Seve ra l m edic atio ns in clu din g busp iro ne , b enzo dia ze pin es, s tim ula nts , a
s e co nd S SR I, a ty p ic al a ntip sych otic s, a nd tr ic yclic a ntid epre ssa nts ( T C As) h ave b een p ro pose d
fo r a ugm enta tio n o f S SR I/S N RI tr e atm ent o f p edia tr ic a nxie ty d is ord ers ; h ow eve r, th ere is
m inim al to n o e vid ence to s u pport th ese s tr a te gie s [ 2 9,3 0 ].
E vid ence fr o m c lin ical tr ia ls s u ggests th a t a ugm enta tio n o f p harm aco th era py w ith c o gnitiv e
behavio ra l th era py ( C BT) m ay b e e ff e ctiv e in p edia tr ic a nxie ty d is ord ers . ( S ee 'C om bin ing
m edic atio n a nd p sych oth era py' b elo w a nd "P sych oth era py fo r a nxie ty d is ord ers in c h ild re n a nd
adole sce nts ", s e ctio n o n 'C om bin ing m edic atio n a nd p sych oth era py' .)
T ric yclic a n tid ep re ssan ts — We d o n ot g enera lly u se T C As in fir st- o r s e co nd-lin e tr e atm ent
of a nxie ty d is ord ers in c h ild re n, b eca use o f th e lim ite d s u pport fr o m c lin ical tr ia ls a nd s id e e ff e ct
p ro file th at is ty p ic ally le ss w ell- to le ra te d th an S SR Is .
E ffic acy — Clin ical tr ia ls h ave fo und m ixed r e su lts o n th e e ff ic acy o f T C As in p edia tr ic
a nxie ty d is ord ers :
S ep ara tio n a n xie ty d is o rd er — A s ix -w eek c lin ical tr ia l in 2 1 y o uth s ( a ges 6 to 1 5) w ith
se para tio n a nxie ty d is ord er c o m pare d im ipra m ine w ith p la ce bo, fin din g n o d iffe re nce in th e
re sp onse r a te b etw een th e tw o g ro ups ( 4 5 v e rs u s 4 4 p erc e nt) [ 3 1 ].

Mix ed a n xie ty d is o rd ers — C lin ical tr ia ls h ave fo und th at im ipra m ine r e duce d a nd
clo m ipra m ine d id n ot r e duce s ym pto m s in a s a m ple o f y o uth w ith m ixed a nxie ty d is ord ers
( o ve ra nxio us d is ord er [G AD in D SM -IV a nd D SM -5 ], s e para tio n a nxie ty d is ord er, o r s ch ool
re fu sa l):
A dvers e e ffe cts — Antic holin erg ic e ff e cts a re fr e quently o bse rv e d in c h ild re n a nd
adole sce nts ta kin g T C As. D ry m outh a nd c o nstip atio n h ave b een fo und to b e c o m mon in b oth
c h ild re n/a dole sce nts a nd a dults [ 3 4 ]. B lu rre d v is io n a nd u rin ary r e te ntio n h ave b een fo und le ss
fr e quently in c h ild re n a nd a dole sce nts c o m pare d w ith a dults. Ir rit a bilit y a nd a nger o utb urs ts
w ere fo und to b e c o m mon a dve rs e e ff e cts o f im ipra m ine .
TC As c a n le ad to ir re gula r o r r a pid h eartb eat in s o m e in div id uals . P rio r to s ta rtin g a T C A,
ch ild re n s h ould r e ce iv e a c a rd ia c r is k a sse ssm ent c o nsis tin g o f a b ase lin e e le ctr o ca rd io gra m ,
vita l sig ns, a nd b ase lin e la bs. A lte rn ativ e m edic atio ns s h ould b e u se d in p atie nts w ith a n
ele va te d c a rd ia c r is k. ( S ee "T ric yclic a nd te tr a cyclic d ru gs: P harm aco lo gy, a dm inistr a tio n, a nd
sid e e ff e cts " .)
A ntid epre ssa nt m edic atio ns a re a sso cia te d w ith a n in cre ase d r is k o f s u ic id alit y in c h ild re n,
w hic h w e a ddre ss b elo w. ( S ee 'S uic id alit y a nd a ntid epre ssa nts in c h ild re n' b elo w.)
S uic id alit y a n d a n tid ep re ssan ts in c h il d re n — There is a n in cre ase d r is k o f s u ic id al th in kin g
and b ehavio r in c h ild re n a nd a dole sce nts ta kin g a ntid epre ssa nt m edic atio ns, a r is k th at s h ould
be w eig hed a gain st th e p ote ntia l b enefit s o f th e m edic atio n. T he U S F ood a nd D ru g
A dm inistr a tio n is su ed a “ b la ck b ox” w arn in g in 2 004, s ta tin g th at c h ild re n a nd a dole sce nts
ta kin g a ntid epre ssa nt m edic atio n, in clu din g S SR Is a nd T C As, a re a t in cre ase d r is k fo r s u ic id al
th in kin g o r b ehavio r [ 3 5 ]. A ntid epre ssa nt r is ks a nd th e eva lu atio n/m anagem ent o f s u ic id alit y in
c h ild re n a re d is cu sse d in m ore d eta il se pa ra te ly .
A m eta -a naly sis o f 3 9 m edic atio n tr ia ls c o nducte d in c h ild re n a nd a dole sce nts tr e ate d w ith a n
S SR Is , S N RIs , n efa zo done , v e nla fa xin e , o r m irta za pin e fo r a n a nxie ty d is ord er ( in clu din g
obse ssiv e-c o m puls ive d is ord er [O CD] u nd er D SM -IV ) s h ow ed a s m all in cre ase in th e r is k o f
su ic id al id eatio n a nd s u ic id e a tte m pts c o m pare d w ith th ose a ssig ned to p la ce bo ( 0 .5 p erc e nt fo r
O CD; 0 .7 p erc e nt fo r a nxie ty d is ord ers o th er th an O CD ) [ 3 6 ]. T he n um ber n eeded to h arm w as
200 fo r O CD a nd 1 43 fo r n on-O CD a nxie ty d is ord ers . T here w ere n o c o m ple te d s u ic id es
re porte d in th e tr ia ls s tu die d. T he m eta -a n aly sis in dic ate d g ood e ff ic acy fo r th e a ntid epre ssa nts
in th e tr e atm ent o f p edia tr ic a nxie ty d is ord ers , w ith a n um ber-n eeded-to -tr e at o f s ix fo r O CD
and th re e fo r n on-O CD a nxie ty d is ord ers . Y ou th w ith O CD w ere 3 3 tim es m ore lik ely to b enefit
A s ix -w eek, r a ndom ized tr ia l co m pare d im ipra m ine w ith p la ce bo in 3 5 y o uth s ( a ges 6 to 1 4)
w ith s e para tio n a nxie ty d is ord er le adin g to s ch ool re fu sa l [ 3 2 ]. P sych ia tr is t r a tin gs fo und
th at p artic ip ants w ho r e ce iv ed im ipra m ine h ad a m ark e d d ecre ase in s ym pto m s c o m pare d
w ith p atie nts w ho r e ce iv ed p la ce bo ( 7 3 v e rs u s 3 2 p erc e nt o n a g lo bal im pro ve m ent s ca le ).
C hild re n r e ce iv in g im ipra m ine w ere m ore lik ely to r e gula rly a tte nd s ch ool a t p ost- tr e atm ent
co m pare d w ith c h ild re n in th e p la ce bo g ro up ( 8 1 v e rs u s 4 7 p erc e nt) .

A tw elv e-w eek c lin ical tr ia l co m parin g clo m ipra m ine w ith p la ce bo in 5 1 y o uth s ( a ges 9 to
1 4) w ith o ve ra nxio us d is ord er, s e para tio n a nxie ty d is ord er, o r s ch ool re fu sa l d id n ot fin d a
d iffe re nce in r e sp onse r a te s b etw een th e t w o g ro ups [ 3 3 ].


fr o m a ntid epre ssa nt tr e atm ent th an to e xp erie nce a s u ic id al e ve nt. F or y o uth w ith a nxie ty
d is ord ers o th er th an O CD, tr e atm ent b enefit w as 4 7 tim es m ore lik ely th an a s u ic id al e ve nt.
A noth er m eta -a naly sis e va lu ate d th e s u ic id alit y o f n in e a ntid epre ssa nts in a to ta l o f 2 4
ra ndom ized c o ntr o lle d tr ia ls o f c h ild re n w ith p edia tr ic a nxie ty d is ord ers , d epre ssio n, o r a tte ntio n
defic it h yp era ctiv ity d is ord er. T he r is k r a tio ( R R) o f s u ic id alit y a cro ss tr ia ls w as R R = 1 .9 5, 9 5%
C I, 1 .2 8-2 .9 8 [ 3 7 ]. C hild s u ic id alit y a nd a ntid epre ssa nt d ru g s a re d is cu sse d in g re ate r d eta il
se para te ly , a s is th e e va lu atio n a nd m ana gem ent o f s u ic id alit y in c h ild re n. ( S ee "S uic id al
id eatio n a nd b ehavio r in c h ild re n a nd a dole sce nts : E va lu atio n a nd m anagem ent" a nd "E ff e ct o f
antid epre ssa nts o n s u ic id e r is k in c h ild re n a nd a dole sce nts " .)
T he lo ng-te rm e ff e cts o f c h ro nic a ntid epre ssa nt m edic atio n u se in c h ild re n a nd a dole sce nts a re
n ot k n ow n [ 2 8 ].
In r e portin g o n th e a sso cia tio n b etw een a ntid epre ssa nts a nd s u ic id e, th e U S F D A
re co m mended th at th e m edic atio ns b e s ta rte d a t lo w d ose s a nd in cre ase d g ra dually [ 2 8 ]. A n
exa m ple is p ro vid ed a bove . ( S ee 'A dm inistr a tio n' a bove .)
T he F D A a dditio nally r e co m mended c lo se m onito rin g o f p atie nt’s c lin ical sta tu s d urin g th e e arly
w eeks o f a ntid epre ssa nt tr e atm ent a nd lim itin g th e d ura tio n o f th eir u se . W e a gre e w ith th e
re co m mendatio n th at c h ild re n p re scrib ed a n a ntid epre ssa nt m edic atio n s h ould m eet w ith th e
pre scrib ing c lin icia n:
P atie nts s h ould b e s e en m ore fr e quently t h an m onth ly m ain te nance v is its if th ey e xp erie nce a n
acu te in cre ase in s ym pto m s o r d eclin e in fu nctio nin g, if m edic atio ns a re b ein g a dju ste d o r
ch anged, o r if th e p atie nt is e xp erie ncin g s u ic id al th oughts /b ehavio r o r c o nsu m ing a lc ohol o r
illic it s u bsta nce s.
T he U S F D A r e co m mended a m edic atio n-fr e e tr ia l o f p atie nts w ho e xp erie nce d im inished
anxie ty o nce th e r e ductio n is m ain ta in ed fo r m ore th an a y e ar. A tim e p erio d w hen th e c h ild h as
lo wer s tr e ss ( e g, s ch ool va ca tio n) is r e co m mended fo r th e tr ia l. T he m edic atio n s h ould b e
re su m ed if th e p atie nt e xp erie nce s a r e la pse o f s ym pto m s a fte r th e m edic atio n h as b een
sto pped [ 2 8 ].
B EN ZO DIA ZE PIN ES — Benzo dia ze pin es h ave a lim ite d r o le in th e tr e atm ent o f p edia tr ic
a nxie ty d is ord ers . T hey h ave a r a pid o nse t o f a nxio lysis ( m inute s to h ours ) c o m pare d w ith
a ntid epre ssa nts , w hic h c a n ta ke a s lo ng a s s e ve ra l w eeks. B enzo dia ze pin es a re , h ow eve r,
a sso cia te d w ith s ig nific ant a dve rs e e ff e cts a nd th eir u se in th is p opula tio n s h ould b e lim ite d.
(S ee 'S SR I/S N RI' a bove a nd "P sych oth era py fo r a nxie ty d is ord ers in c h ild re n a nd
adole sce nts " .)
In dic atio ns fo r b enzo dia ze pin e tr e atm ent in p edia tr ic a nxie ty d is ord ers a re d is cu sse d b elo w.
(S ee 'T re atm ent s e le ctio n' b elo w.)
W eekly fo r th e fir st fo ur w eeks ●
B iw eekly b egin nin g th e s e co nd m onth ●
M onth ly b egin nin g th e th ird m onth ( ie , 1 2 w eeks fo llo win g th e s ta rt o f m edic atio n) ●

Effic acy — In o ur c lin ical e xp erie nce , b enzo dia ze pin es a ppear to b e e ff e ctiv e in s o m e c a se s o f
pedia tr ic a nxie ty d is ord ers .
C lin ical tr ia ls o f b enzo dia ze pin es fo r th ese d is ord ers h ave b een in adequate to a sse ss e ff ic acy.
T ria ls, w hic h h ad m ultip le lim ita tio ns, r e po rte d n o d iffe re nce s in s ym pto m r e ductio n b etw een
benzo dia ze pin es a nd p la ce bo in :
Larg er tr ia ls a re n eeded th at a sse ss h ig her d osa ges a nd lo nger tr e atm ent p erio ds, a nd e m plo y
str u ctu re d d ia gnosis a nd g ra dual ta perin g p erio ds.
C lin ical tr ia ls o f b enzo dia ze pin es fo r a nxie ty d is ord ers in a dults p ro vid e in dire ct e vid ence fo r
eff ic acy in c h ild re n [ 4 1,4 2 ].
A dvers e e ffe cts — Com mon a dve rs e e ff e cts o f b enzo dia ze pin es in clu de d ro w sin ess, ir rit a bilit y
and o ppositio nal b ehavio r [ 4 3 ]. B enzo dia ze pin es c a n b e s u bje ct to a buse , a ddic tio n, a nd
div ers io n. ( S ee "P re scrip tio n d ru g m isuse : E pid em iology, p re ve ntio n, id entif ic atio n, a nd
m anagem ent" .)
A dm in is tr a tio n — Benzo dia ze pin es w ith lo nger h alf-liv es a re g enera lly s u ggeste d, a s is a
g ra dual tit ra tio n u p fr o m a lo w s ta rtin g d o se . A s a n e xa m ple , c lo naze pam c a n b e s ta rte d a t 0 .2 5
m g/d ay to o bse rv e r e sp onse . T he d ose c a n b e in cre ase d to 0 .5 m g/d ay if w ell- to le ra te d; fu rth er
in cre ase s a re b ase d o n r e sp onse a nd to le ra bilit y
OTH ER M ED IC ATIO NS — A 2 016 p ilo t s tu dy c o m parin g guanfa cin e w ith p la ce bo in 8 3 y o uth
a ges 6 to 1 7 w ith G AD , s e para tio n a nxie ty d is ord er, o r s o cia l a nxie ty d is ord er fo und th at
guanfa cin e w as a sso cia te d w ith g re ate r im pro ve m ent th an p la ce bo a cco rd in g to th e C lin ical
G lo bal Im pre ssio n o f Im pro ve m ent S ca le , b ut n ot o n o th er m easu re s o f a nxie ty . G uanfa cin e
was w ell- to le ra te d in th e s tu dy [ 4 4 ].
B usp iro ne w as fo und to h ave n o d iffe re nce in p rim ary o utc o m es c o m pare d w ith p la ce bo in th e
tr e atm ent o f p edia tr ic g enera liz ed a nxie ty d is ord er in tw o c lin ical tr ia ls w ith a to ta l o f 5 59
patie nts a ges 6 to 1 7 [ 4 5 ]. N ause a, h eadach es, a nd s to m ach a ch e s w ere r e porte d b y y o uth
tr e ate d w ith b usp iro ne.
C O M PA RIN G M ED IC ATIO N A ND P SYC H O TH ER APY — Clin ical tr ia ls c o m parin g s e ro to nin
re upta ke in hib ito r ( S R I) m edic atio n v e rs u s c o gnitiv e b ehavio ra l th era py ( C BT) fo r p edia tr ic
a nxie ty d is ord ers in c h ild re n h ave y ie lded m ixed r e su lts, w hic h a re d escrib ed s e para te ly . ( S ee
"P sych oth era py fo r a nxie ty d is ord ers in c h ild re n a nd a dole sce nts ", s e ctio n o n 'C om parin g
m edic atio n a nd p sych oth era py' .)
C O M BIN IN G M ED IC ATIO N A ND P SYC H O TH ER APY — A c lin ical tr ia l co m parin g c o gnitiv e
behavio ra l th era py ( C BT) to s e le ctiv e s e ro to nin r e upta ke in hib ito r ( S SR I) tr e atm ent in p edia tr ic
8 - to 1 6-y e ar-o ld s w ith o ve ra nxio us d is ord er ( re nam ed g enera liz ed a nxie ty d is ord er [G AD ]
in D SM -IV ) [ 3 8 ]

7- to 1 3-y e ar-o ld s w ith s e para tio n a nxie ty d is ord er w ith o r w ith out c o -o ccu rrin g a nxie ty
d is ord ers [ 3 9 ]

7- to 1 8-y e ar-o ld s w ith G AD , s e para tio n a nxie ty d is ord er, o r s ch ool re fu sa l [ 4 0 ] ●

anxie ty d is ord ers fo und th at c o m bin ed tr e a tm ent w as s u perio r to e ith er m odalit y d eliv ere d
in div id ually ; th ese r e su lts a re d escrib ed s e p ara te ly . ( S ee "P sych oth era py fo r a nxie ty d is ord ers
in c h ild re n a nd a dole sce nts ", s e ctio n o n 'C om bin ing m edic atio n a nd p sych oth era py' .)
T R EATM EN T S ELE C TIO N — Evid ence fr o m c lin ical tr ia ls o n th e tr e atm ent o f p edia tr ic a nxie ty
d is ord ers is , in g enera l, in adequate to fu lly in fo rm s e le ctio n a m ong tr e atm ent o ptio ns,
p artic ula rly fo r s e co nd- a nd th ird -lin e d ecis io ns. S om e a nxie ty d is ord ers ( p anic d is ord er,
a gora phobia , s p ecific p hobia s, a nd s e le ctiv e m utis m ) h ave n ot b een s u bje ct to c lin ical tr ia ls in
c h ild re n. In m any c a se s, a va ila ble tr ia ls h a ve h ad s m all sa m ple s. H ead-to -h ead tr ia ls o f
eff ic acio us d ru gs h ave n ot b een p erfo rm ed. O ur r e co m mendatio ns a re th us in fo rm ed b y
re se arc h e vid ence w here a va ila ble a s w ell as b y o ur c lin ical e xp erie nce .
F ir s t-lin e t r e atm en t
M ild t o m odera te a n xie ty d is o rd er — We s u ggest c o gnitiv e b ehavio ra l th era py ( C BT)
alo ne ( w ith out m edic atio n) a s a fir st- lin e t r e atm ent o f c h ild re n w ith a ny a nxie ty d is ord er o f m ild
to m odera te s e ve rit y. C lin ical tr ia ls c o m parin g C BT w ith s e le ctiv e s e ro to nin r e upta ke in hib ito r
(S SR I) tr e atm ent fo r a p edia tr ic a nxie ty d is ord er a re m ixed, w ith th e la rg est tr ia l fin din g n o
diffe re nce in r e m issio n r a te s b etw een g ro up s a nd a noth er fin din g C BT to b e s u perio r to
s e rtr a lin e . S ele ctio n b etw een th ese m odalit ie s m ay a ls o b e in flu ence d b y a va ila bilit y o f C BT
and b y ch ild /p are nt p re fe re nce s. ( S ee 'C om parin g m edic atio n a nd p sych oth era p y' a bove a nd
"P sych oth era py fo r a nxie ty d is ord ers in c h ild re n a nd a dole sce nts " a nd "P sych oth era py fo r
anxie ty d is ord ers in c h ild re n a nd a dole sc e nts ", s e ctio n o n 'C om parin g m edic atio n a nd
psych oth era py' .)
S evere a n xie ty d is o rd er — For c h ild re n w ith a s e ve re p edia tr ic a nxie ty d is ord er, w e
su ggest fir st- lin e tr e atm ent w ith a c o m bin atio n o f C BT a nd a n S SR I. C om bin ed C BT-S SR I
tr e atm ent p erfo rm ed b ette r th an e ith er m od alit y in div id ually in c lin ical tr ia ls o f c h ild re n w ith
so cia l p hobia , g enera liz ed a nxie ty d is ord er ( G AD ), o r s e para tio n a nxie ty d is ord er [ 4 6 ] a s w ell as
in a tr ia l o f a r e la te d c h ild hood c o nditio n, s ch ool re fu sa l [ 4 7 ]. ( S ee 'S SR I/S N RI' a bove a nd
'C om bin ing m edic atio n a nd p sych oth era p y' a bove a nd "P sych oth era py fo r a nxie ty d is ord ers in
c h ild re n a nd a dole sce nts " a nd "P sych oth era py fo r a nxie ty d is ord ers in c h ild re n a nd
adole sce nts ", s e ctio n o n 'C om bin ing m edic atio n a nd p sych oth era py' .)
C o-o ccu rrin g a n xie ty d is o rd er a n d m ajo r d ep re ssio n — A c o m bin atio n o f C BT a nd S SR I
m edic atio n m ay b e b enefic ia l fo r c h ild re n w ith a n a nxie ty d is ord er a nd c o m orb id m ajo r
depre ssio n, a lth ough th is tr e atm ent c o m bin atio n h as n ot b een te ste d d ire ctly in c lin ical tr ia ls.
Seco nd-lin e t r e atm en t — For a p atie nt w ith a p edia tr ic a nxie ty d is ord er th at d oes n ot r e sp ond
to a n a dequate tr ia l o f C BT, w e s u ggest t r e atm ent w ith a n S SR I r a th er th an o th er m edic atio ns.
S SR Is a nd ve nla fa xin e , a s e ro to nin -n ore pin ephrin e r e upta ke in hib ito r ( S N RI) , h ave b een fo und
to b e e ff ic acio us in c lin ical tr ia ls o f p edia tr ic a nxie ty d is ord ers . T here a re n o h ead to h ead tr ia ls
co m parin g m edic atio ns fo r th e d is ord ers . S SR Is a re m ost e xte nsiv ely s tu die d c la ss a nd a re
g enera lly b ette r to le ra te d th an th e o th er a ntid epre ssa nts . ( S ee 'S SR I/S N RI' a bove a nd 'T ric yclic
a ntid epre ssa nts ' a bove .)
T hir d -lin e t r e atm en t — For p atie nts w hose s ym pto m s d o n ot r e m it a fte r a s ix to e ig ht w eek
tr ia l o n a m axim um to le ra te d d ose o f a n S SR I, w e s u ggest tr e atm ent w ith a s e co nd S SR I p rio r

to u sin g o ne o f th e o th er m edic atio ns w ith s u pport fr o m c lin ical tr ia ls in p edia tr ic a nxie ty
d is ord ers .
V enla fa xin e , a n S N RI, is a r e aso nable o ptio n if tw o S SR I tr ia ls b oth le ad to in adequate c lin ical
re sp onse s.
S SR Is a re g enera lly p re fe rre d to b enzo d ia ze pin es fo r lo ng-te rm tr e atm ent o f a p edia tr ic a nxie ty
d is ord er, th ough b enzo dia ze pin es c a n b e u se fu l in th ese p atie nts to tr e at d is ablin g a nxie ty w hile
w aitin g fo r a n a ntid epre ssa nt to ta ke e ff e ct, o r to tr e at S SR I- in duce d jit te rin ess. ( S ee
'B enzo dia ze pin es' a bove .)
S O CIE TY G UID ELIN E L IN KS — Lin ks to s o cie ty a nd g ove rn m ent- s p onso re d g uid elin es fr o m
se le cte d c o untr ie s a nd r e gio ns a ro und th e w orld a re p ro vid ed s e para te ly . ( S ee "S ocie ty
g uid elin e lin ks: A nxie ty d is ord ers in c h ild re n" .)
S U M MARY A ND R EC O M MEN DATIO NS
W e s u ggest fir st- lin e tr e atm ent o f c h ild re n w ith a m ild to m odera te a nxie ty d is ord er w ith
co gnitiv e b ehavio ra l th era py ( C BT) r a th er th an m edic atio n ( G ra d e 2 B ). M edic atio n
tr e atm ent w ould b e a r e aso nable a lte rn a tiv e if p re fe rre d b y th e p atie nt o r if C BT w ere
u nava ila ble . ( S ee "P sych oth era py fo r a nxie ty d is ord ers in c h ild re n a nd a dole sce nts ",
s e ctio n o n 'C om parin g m edic atio n a nd p sych oth era py' a nd 'M ild to m odera te a nxie ty
d is ord er' a bove .)

F or a p atie nt w ith a p edia tr ic a nxie ty d is ord er th at d oes n ot r e sp ond to a n a dequate tr ia l o f
C BT, w e s u ggest fir st- lin e tr e atm ent w ith a s e le ctiv e s e ro to nin r e upta ke in hib ito r ( S SR I)
r a th er th an o th er m edic atio ns ( G ra d e 2 C ). ( S ee 'A ntid epre ssa nts ' a bove .)

A s a n e xa m ple , s e rtr a lin e c a n b e s ta rte d a t a n in itia l d ose o f 1 2.5 to 2 5 m g/d ay fo r a
m inim um o f s e ve n d ays a nd tit ra te d u p to 5 0 m g/d ay in in cre m ents o f 1 2.5 m g ( c h ild )
or 2 5 to 5 0 m g ( a dole sce nt) p er w eek. If a n a dequate c lin ical re sp onse is n ot s e en
afte r s ix to e ig ht w eeks o f tr e atm ent, s u bse quent tr ia ls s h ould b e tr ie d fo llo win g d ose
in cre ase s o f 1 2.5 m g/d ay fo r c h ild re n a nd 2 5 to 5 0 m g/d ay fo r a dole sce nts to a
m axim um o f 2 00 m g/d ay . ( S ee 'A dm inistr a tio n' a bove .)

A ta ble s u m mariz es in itia l d aily d ose s, th era peutic r a nges, a nd s u ggeste d d ose
tit ra tio n r a te s fo r p harm aco th era py in a nxie ty d is ord ers in c h ild re n ( ta ble 1 ) .

F or c h ild re n w ith a s e ve re a nxie ty d is ord e r, w e s u ggest fir st- lin e tr e atm ent w ith a
c o m bin atio n o f C BT a nd a n S SR I r a th er t h an e ith er m odalit y a s m onoth era py o r o th er
tr e atm ents ( G ra d e 2 B ). ( S ee "P sych oth era py fo r a nxie ty d is ord ers in c h ild re n a nd
adole sce nts ", s e ctio n o n 'C om bin ing m edic atio n a nd p sych oth era py' a nd 'T re atm ent
se le ctio n' a bove .)

W hen s to ppin g a n S SR I, d ecre ase th e d ose g ra dually ( e g, b y 2 5 to 5 0 p erc e nt w eekly ) to
a vo id d is co ntin uatio n s ym pto m s. D urin g th e ta perin g p erio d, th e tr e atin g c lin icia n s h ould
ca re fu lly m onito r th e c h ild o r a dole sce nt fo r a dve rs e e ve nts .


Use o f U pTo D ate is s u bje ct to th e S ubscrip tio n a nd L ic ense A gre em ent .
R EFE R EN CES
1. C oste llo E J, M ustillo S , E rk a nli A, e t a l. P re va le nce a nd d eve lo pm ent o f p sych ia tr ic
d is ord ers in c h ild hood a nd a dole sce nce . A rc h G en P sych ia tr y 2 003; 6 0:8 37.
2. M erik angas K R , H e J P , B urs te in M , e t a l. L ife tim e p re va le nce o f m enta l d is ord ers in U .S .
adole sce nts : r e su lts fr o m th e N atio nal C om orb id ity S urv e y R eplic atio n--A dole sce nt
S upple m ent ( N CS-A ). J A m A ca d C hild A dole sc P sych ia tr y 2 010; 4 9:9 80.
3. H ughes A A, L oure a-W addell B, K endall PC . S om atic c o m pla ints in c h ild re n w ith a nxie ty
d is ord ers a nd th eir u niq ue p re dic tio n o f p oore r a ca dem ic p erfo rm ance . C hild P sych ia tr y
H um D ev 2 008; 3 9:2 11 .
4. Ia lo ngo N , E dels ohn G , W erth am er-L ars so n L , e t a l. T he s ig nific ance o f s e lf-re porte d
anxio us s ym pto m s in fir st g ra de c h ild re n: p re dic tio n to a nxio us s ym pto m s a nd a daptiv e
fu nctio nin g in fif th g ra de. J C hild P sych o l P sych ia tr y 1 995; 3 6:4 27.
5. G rills A E, O lle ndic k T H . P eer v ic tim izatio n, g lo bal se lf-w orth , a nd a nxie ty in m iddle s ch ool
ch ild re n. J C lin C hild A dole sc P sych ol 2 0 02; 3 1:5 9.
F or p atie nts w hose s ym pto m s d o n ot r e m it a fte r a s ix - to e ig ht- w eek tr ia l o n a m axim um
to le ra te d d ose o f a n S SR I, w e s u ggest tr e atm ent w ith a s e co nd S SR I r a th er th an o th er
m edic atio n s tr a te gie s ( G ra d e 2 C ). T he tr ic yclic a ntid epre ssa nts ( T C As; c lo m ipra m ine a nd
im ipra m ine ), s e ro to nin -n ore pin ephrin e r e upta ke in hib ito r ( S N RI; v e nla fa xin e ), a nd
benzo dia ze pin es a ll have d is adva nta ges r e la tiv e to S SR Is ; th eir u se s h ould b e lim ite d to
s p ecific c lin ical cir cu m sta nce s w ith w ell- de fin ed r a tio nale s ( ta ble 1 ) . ( S ee
'B enzo dia ze pin es' a bove a nd 'A ugm enta tio n' a bove a nd 'T ric yclic a ntid epre ssa nts ' a bove .)

V enla fa xin e , a n S N RI, is a r e aso nable o ptio n if tw o S SR I tr ia ls b oth le ad to in adequate
c lin ical re sp onse s. V enla fa xin e c a n b e s ta rte d a t 3 7.5 m g/d ay fo r a m inim um o f s e ve n
days a nd in cre ase d in in cre m ents o f 3 7.5 m g/d ay in a c h ild o r 7 5 m g/d ay in a n
adole sce nt e ve ry fo ur w eeks, a nd d epen din g o n r e sp onse a nd to le ra bilit y, to a n in itia l
th era peutic d ose o f 1 50 m g/d ay . ( S ee 'A dm inistr a tio n' a bove .)

W hen ta kin g ve nla fa xin e , c h ild re n s h ould b e m onito re d fo r w eig ht g ain , e le va te d
ch ole ste ro l, a nd h yp erte nsio n, w hic h h ave b een r e porte d in s o m e p atie nts . ( S ee
'A dve rs e e ff e cts ' a bove .)
L onger-a ctin g b enzo dia ze pin es c a n b e u se fu l in c h ild re n w ith a nxie ty d is ord ers to tr e at
dis ablin g a nxie ty w hile w aitin g fo r a n a ntid epre ssa nt to ta ke e ff e ct o r to tr e at S SR I-
in duce d jit te rin ess. ( S ee 'B enzo dia ze pin es' a bove .)

A s a n e xa m ple , c lo naze pam c a n b e s ta rte d a t 0 .2 5 m g/d ay to o bse rv e r e sp onse . T he
dose c a n b e in cre ase d to 0 .5 m g/d ay if w ell to le ra te d; fu rth er in cre ase s a re b a se d o n
re sp onse a nd to le ra bilit y.

6. B ra dy E U , K endall PC . C om orb id ity o f a nxie ty a nd d epre ssio n in c h ild re n a nd
adole sce nts . P sych ol B ull 1992; 1 11 :2 44 .
7. C om pto n W M, T hom as Y F, S tin so n F S , G ra nt B F. P re va le nce , c o rre la te s, d is abilit y, a nd
co m orb id ity o f D SM -IV d ru g a buse a nd d ep endence in th e U nite d S ta te s: r e su lts fr o m th e
natio nal e pid em iologic s u rv e y o n a lc ohol a nd r e la te d c o nditio ns. A rc h G en P sych ia tr y
2 007; 6 4:5 66.
8. K endall PC , S aff o rd S , F la nnery -S ch ro ede r E , W ebb A . C hild a nxie ty tr e atm ent: o utc o m es
in a dole sce nce a nd im pact o n s u bsta nce u se a nd d epre ssio n a t 7 .4 -y e ar fo llo w-u p. J
C onsu lt C lin P sych ol 2 004; 7 2:2 76.
9. M erik angas K R , A m es M , C ui L , e t a l. T he im pact o f c o m orb id ity o f m enta l a nd p hysic al
co nditio ns o n r o le d is abilit y in th e U S a dult h ouse hold p opula tio n. A rc h G en P sych ia tr y
2 007; 6 4:1 1 80.
10 . B oden J M , F erg usso n D M , H orw ood L J. A nxie ty d is ord ers a nd s u ic id al b ehavio urs in
a dole sce nce a nd y o ung a dulth ood: fin din gs fr o m a lo ngitu din al stu dy. P sych ol M ed 2 007;
37:4 31.
11 . U th m an O A, A bdulm alik J . C om para tiv e e ff ic acy a nd a cce pta bilit y o f p harm aco th era peutic
a gents fo r a nxie ty d is ord ers in c h ild re n a nd a dole sce nts : a m ixed tr e atm ent c o m paris on
m eta -a naly sis . C urr M ed R es O pin 2 010; 2 6:5 3.
12 . R yn n M A, S iq uela nd L , R icke ls K . P la ce b o-c o ntr o lle d tr ia l o f s e rtr a lin e in th e tr e atm ent o f
ch ild re n w ith g enera liz ed a nxie ty d is ord er. A m J P sych ia tr y 2 001; 1 58:2 008.
13 . S tr a w n J R , P ra ka sh A , Z hang Q , e t a l. A r a ndom ized, p la ce bo-c o ntr o lle d s tu dy o f
dulo xe tin e fo r th e tr e atm ent o f c h ild re n a n d a dole sce nts w ith g enera liz ed a nxie ty d is ord er.
J A m A ca d C hild A dole sc P sych ia tr y 2 015 ; 5 4:2 83.
14 . R yn n M A, R id dle M A, Y eung P P, K unz N R . E ff ic acy a nd s a fe ty o f e xte nded-re le ase
ve nla fa xin e in th e tr e atm ent o f g enera liz ed a nxie ty d is ord er in c h ild re n a nd a dole sce nts :
tw o p la ce bo-c o ntr o lle d tr ia ls. A m J P sych ia tr y 2 007; 1 64:2 90.
15 . W agner K D , B era rd R , S te in M B, e t a l. A m ultic ente r, r a ndom ized, d ouble -b lin d, p la ce bo-
co ntr o lle d tr ia l o f p aro xe tin e in c h ild re n a n d a dole sce nts w ith s o cia l a nxie ty d is ord er. A rc h
G en P sych ia tr y 2 004; 6 1:1 1 53.
16 . M arc h J S , E ntu sa h A R , R yn n M , e t a l. A R andom ized c o ntr o lle d tr ia l o f v e nla fa xin e E R
ve rs u s p la ce bo in p edia tr ic s o cia l a nxie ty d is ord er. B io l P sych ia tr y 2 007; 6 2:1 1 49.
17 . B eid el D C, T urn er S M , S alle e F R , e t a l. S ET-C v e rs u s flu oxe tin e in th e tr e atm ent o f
ch ild hood s o cia l p hobia . J A m A ca d C hild A dole sc P sych ia tr y 2 007; 4 6:1 622.
18 . B la ck B , U hde T W . T re atm ent o f e le ctiv e m utis m w ith flu oxe tin e: a d ouble -b lin d, p la ce bo-
co ntr o lle d s tu dy. J A m A ca d C hild A dole sc P sych ia tr y 1 994; 3 3:1 000.
19 . C arls on J S , K ra to ch w ill TR , J o hnsto n H F. S ertr a lin e tr e atm ent o f 5 c h ild re n d ia gnose d
w ith s e le ctiv e m utis m : a s in gle -c a se r e se arc h tr ia l. J C hild A dole sc P sych opharm aco l
1999; 9 :2 93.
20 . D um mit E S 3 rd , K le in R G , T a nce r N K, e t a l. F lu oxe tin e tr e atm ent o f c h ild re n w ith s e le ctiv e
m utis m : a n o pen tr ia l. J A m A ca d C hild A dole sc P sych ia tr y 1 996; 3 5:6 15.

21 . R enaud J , B irm aher B , W assic k S C , B rid ge J . U se o f s e le ctiv e s e ro to nin r e upta ke
in hib ito rs fo r th e tr e atm ent o f c h ild hood p a nic d is ord er: a p ilo t s tu dy. J C hild A dole sc
P sych opharm aco l 1 999; 9 :7 3.
22 . M asi G , T o ni C , M ucci M , e t a l. P aro xe tin e in c h ild a nd a dole sce nt o utp atie nts w ith p anic
dis ord er. J C hild A dole sc P sych opharm aco l 2 001; 1 1 :1 51.
23 . F airb anks J M , P in e D S, T a nce r N K, e t a l. O pe n flu oxe tin e tr e atm ent o f m ixed a nxie ty
d is ord ers in c h ild re n a nd a dole sce nts . J C hild A dole sc P sych opharm aco l 1 997; 7 :1 7.
24 . G halib K D , V id air H B, W oodco m e H A, e t a l.. A nxie ty d is ord ers . In : P edia tr ic P sych opharm
a co lo gy: P rin cip les a nd P ra ctic e, 2 nd e d , O xfo rd U niv ers ity P re ss, L ondon 2 011 .
25 . F lu vo xa m ine fo r th e tr e atm ent o f a nxie ty d is ord ers in c h ild re n a nd a dole sce nts . T he
R ese arc h U nit o n P edia tr ic P sych opharm aco lo gy A nxie ty S tu dy G ro up. N E ngl J M ed
2001; 3 44:1 279.
26 . W alk up J T, A lb ano A M , P ia ce ntin i J, e t a l. C ognitiv e b ehavio ra l th era py, s e rtr a lin e, o r a
c o m bin atio n in c h ild hood a nxie ty . N E ngl J M ed 2 008; 3 59:2 753.
27 . B irm aher B , A xe ls on D A, M onk K , e t a l. F lu oxe tin e fo r th e tr e atm ent o f c h ild hood a nxie ty
d is ord ers . J A m A ca d C hild A dole sc P sy ch ia tr y 2 003; 4 2:4 15.
28 . R yn n M , P ulia fic o A , H ele nia k C , e t a l. A dva nce s in p harm aco th era py fo r p edia tr ic a nxie ty
d is ord ers . D epre ss A nxie ty 2 011 ; 2 8:7 6.
29 . C onnolly S D , B ern ste in G A, W ork G ro up o n Q ua lit y Is su es. P ra ctic e p ara m ete r fo r th e
asse ssm ent a nd tr e atm ent o f c h ild re n a nd a dole sce nts w ith a nxie ty d is ord ers . J A m A ca d
C hild A dole sc P sych ia tr y 2 007; 4 6:2 67.
30 . B irm aher B , Y elo vic h A K, R enaud J . P harm aco lo gic tr e atm ent fo r c h ild re n a nd
adole sce nts w ith a nxie ty d is ord ers . P edia tr C lin N orth A m 1 998; 4 5:1 1 87.
31 . K le in R G , K ople wicz H S, K anner A . Im ipra m ine tr e atm ent o f c h ild re n w ith s e para tio n
anxie ty d is ord er. J A m A ca d C hild A dole sc P sych ia tr y 1 992; 3 1:2 1.
32 . G itte lm an-K le in R , K le in D F. C ontr o lle d im ipra m ine tr e atm ent o f s ch ool p hobia . A rc h G en
P sych ia tr y 1 971; 2 5:2 04.
33 . B ern ey T , K olv in I, B hate S R , e t a l. S ch oo l p hobia : a th era peutic tr ia l w ith c lo m ipra m ine
and s h ort- te rm o utc o m e. B r J P sych ia tr y 1 981; 1 38:1 1 0.
34 . R ya n N D. H ete ro cyclic a ntid epre ssa nts in c h ild re n a nd a dole sce nts . J C hild A dole sc
P sych opharm aco l 1 990; 1 :2 1.
35 . A ntid epre ssa nt U se in C hild re n, A dole sce nts , a nd A dults h ttp ://w ww.fd a.g ov/d ru gs/d ru gsa f
ety /in fo rm atio nbyd ru gcla ss/u cm 096273.h tm ( A cce sse d o n O cto ber 0 5, 2 010).
3 6 . B rid ge J A , Iy e ngar S , S ala ry C B, e t a l. C lin ical re sp onse a nd r is k fo r r e porte d s u ic id al
id eatio n a nd s u ic id e a tte m pts in p edia tr ic a ntid epre ssa nt tr e atm ent: a m eta -a naly sis o f
ra ndom ized c o ntr o lle d tr ia ls. J A M A 2 007; 2 97:1 683.
37 . H am mad T A , L aughre n T , R aco osin J . S uic id alit y in p edia tr ic p atie nts tr e ate d w ith
a ntid epre ssa nt d ru gs. A rc h G en P sych ia tr y 2 006; 6 3:3 32.
38 . S im eon J G , F erg uso n H B, K nott V , e t a l. C lin ical, c o gnitiv e, a nd n euro physio logic al e ff e cts
o f a lp ra zo la m in c h ild re n a nd a dole sce nts w ith o ve ra nxio us a nd a vo id ant d is ord ers . J A m

Aca d C hild A dole sc P sych ia tr y 1 992; 3 1:2 9 .
39 . G ra ae F , M iln er J , R izzo tto L , K le in R G . C lo naze pam in c h ild hood a nxie ty d is ord ers . J A m
Aca d C hild A dole sc P sych ia tr y 1 994; 3 3:3 7 2.
40 . B ern ste in G A, G arfin ke l B D , B orc h ard t C M . C om para tiv e s tu die s o f p harm aco th era py fo r
sch ool re fu sa l. J A m A ca d C hild A dole sc P sych ia tr y 1 990; 2 9:7 73.
41 . B alle nger J C , B urro w s G D, D uP ont R L J r, e t a l. A lp ra zo la m in p anic d is ord er a nd
agora phobia : r e su lts fr o m a m ultic ente r tr ia l. I. E ff ic acy in s h ort- te rm tr e atm ent. A rc h G en
P sych ia tr y 1 988; 4 5:4 13.
42 . R icke ls K , C sa nalo si I, G re is m an P , e t a l. A c o ntr o lle d c lin ical tr ia l o f a lp ra zo la m fo r th e
tr e atm ent o f a nxie ty . A m J P sych ia tr y 1 98 3; 1 40:8 2.
43 . M artin A , S ca hill L, K ra to ch vil C. P edia tr ic P sych opharm aco lo gy, O xfo rd U niv ers ity P re ss,
N ew Y ork 2 010. p .4 80.
44 . S tr a w n J R , C om pto n S N , R oberts o n B , e t a l. E xte nded R ele ase G ua nfa cin e in P edia tr ic
A nxie ty D isord ers : A P ilo t, R andom ized, P la ce bo-C ontr o lle d T ria l. J C hild A dole sc
P sych opharm aco l 2 017; 2 7:2 9.
45 . B uS par [p acka ge in se rt] P rin ce to n N J: B ris to l-M ye rs S quib b; 2 010.
46 . G in sb urg G S, K endall PC , S ako ls ky D , e t a l. R em issio n a fte r a cu te tr e atm ent in c h ild re n
and a dole sce nts w ith a nxie ty d is ord ers : f in din gs fr o m th e C AM S. J C onsu lt C lin P sych ol
2011 ; 7 9:8 06.
47 . B ern ste in G A, B orc h ard t C M , P erw ie n A R , e t a l. Im ipra m ine p lu s c o gnitiv e-b ehavio ra l
th era py in th e tr e atm ent o f s ch ool re fu sa l. J A m A ca d C hild A dole sc P sych ia tr y 2 000;
39:2 76.
To pic 1 5928 V ers io n 5 .0

GRAPH IC S
Pharm aco th er ap y fo r a nxiet y d iso rd er s in children and a dolescen ts
Ag ent In it ia l d aily
d ose
Su ggest ed
dose
tit ra tio n
based upon
resp on se
M ain ten an ce
daily dose
ra n ge
Select ed
chara ct er ist ics*
Sele ctiv e s ero to n in re upta k e in hib itors ( SS R Is )*
F lu oxe tin e C hild re n : 5 t o
1 0 m g
Ad ole sce n ts : 1 0
m g
Af te r 7 d ays
in cre a se d aily
d ose t o 2 0 m g;
th en a ft e r 4 a n d
8 w eeks in cre a se
d aily d ose b y 2 0
m g, if n eed ed
1 0 t o 8 0 m g Pro lo n ged h alf - lif e .
M eta b oliz e d b y
an d in hib it s
C YP2 D 6.
Flu vo xa m in e 2 5 t o 5 0 m g a t
b ed tim e
In cre a se d aily
d ose b y 2 5 m g
(c h ild ) o r 2 5 t o
5 0 m g
(a d ole sce n t)
a ft e r a m in im um
of 7 d ays, if
n eed ed
5 0 t o 3 00 m g Gir ls g en era lly
r e q u ir e lo w er
m ain te n an ce
d ose s t h an b oys.
G iv e w it h m ea ls
a n d b ed tim e in
d iv id ed d ose s t o
m in im iz e s id e
effe cts .
M eta b oliz e d b y
C YP1 A2 a n d 2 D 6.
In hib it s C YP1 A2
an d 2 C 19.
Se rtr a lin e 1 2.5 t o 2 5 m g In cre a se d aily
d ose b y 1 2.5 m g
(c h ild ) o r 2 5 t o
5 0 m g
(a d ole sce n t)
a ft e r a m in im um
of 7 d ays, if
n eed ed
5 0 t o 2 00 m g Dia rrh ea m ore
fr e q u en t t h an
o th er S SR Is .
M eta b oliz e d b y
C YP2 D 6.
In hib it s C YP2 D 6
w it h la rg er d ose s.
P a ro xe tin e 5 t o 1 0 m g In cre a se d aily
d ose b y 5 m g
(c h ild ) o r 1 0 m g
(a d ole sce n t)
a ft e r a m in im um
of 7 d ays, if
n eed ed
1 0 t o 6 0 m g Sh ort h alf - lif e .
M ild
a n tic h olin erg ic
s id e e ffe cts .
M eta b oliz e d b y
an d in hib it s
C YP2 D 6.
W eig h t g ain .
S ero to n in nore p in ep h rin e re upta k e in hib itor ( SN RI)*
V en la fa xin e
exte n ded -
re le a se ( E R )
37.5 m g In cre a se d aily
d ose b y 3 7.5 m g
75 t o 2 25 m g Dose -re la te d
in cre a se in
d ia sto lic b lo od

(c h ild ) o r 7 5 m g
(a d ole sce n t)
a ft e r a m in im um
of 7 d ays, if
n eed ed
p re ssu re a n d/o r
h ea rt r a te m ay b e
se en .
Som e c h ild re n
m ay e xp erie n ce
w eig h t lo ss.
M eta b oliz e d b y
C YPs 2 D 6 a n d
3 A4 .
Pro lo n gatio n o f Q t
in te rv a l.
D ulo xe tin e 3 0 m g In cre a se d aily
d ose b y 3 0 m g
aft e r a m in im um
of 1 4 d ays, if
n eed ed
3 0 t o 6 0 m g
Som e p atie n ts
m ay b en efit fr o m
a h ig h er d aily
d ose , in cre a se d
b y 3 0 m g
in cre m en ts e ve ry
2 t o 4 w eeks, t o
m axim um o f 1 20
m g p er d ay
Som e c h ild re n
m ay e xp erie n ce
d ose -re la te d
g astr o in te stin al-
r e la te d a d ve rs e
e ffe cts ( e g ,
n au se a a n d
ab dom in al p ain ),
a n d w eig h t lo ss.
P a lp it a tio n s a n d
in cre a se d p u ls e
w ere o b se rv e d
m ore fr e q u en tly
t h an w it h p la ce b o
in a p ed ia tr ic G AD
tr ia l.
U se w it h s tr o n g
in hib it o rs ( e g ,
flu vo xa m in e) o r
in du ce rs ( e g ,
ca rb am aze p in e,
rif a m pin ) o f
C YP1 A2 s h ou ld in
g en era l b e
avo id ed .
St ro n g C YP2 D 6
in hib it o rs ( e g ,
flu oxe tin e,
p aro xe tin e,
tip ra n avir ) c a n
in cre a se
d u lo xe tin e
co n ce n tr a tio n s b y
u p t o 6 0% .
Tric yclic an tid ep re ssa n ts ( TC A )
Clo m ip ra m in e C hild re n ≥ 10
ye a rs o ld a n d
ad ole sce n ts : 2 5
m g
In cre a se d aily
d ose b y 2 5 m g
aft e r a m in im um
of 7 d ays, if
n eed ed ; g iv e in
d iv id ed d ose s
w it h m ea ls a n d
bed tim e
25 t o 2 50 m g ( 2
to 6 m g/k g p er
d ay); d ose s > 2.5
m g/k g p er d ay
sh ou ld b e u se d
ca u tio u sly
Ap plie s t o
c lo m ip ra m in e a n d
im ip ra m in e:
C ard io va scu la r
scre en in g
in clu din g E C G
re co m men ded
p rio r t o



p
in it ia tin g
tr e a tm en t.
An tic h olin erg ic
s id e e ffe cts m ay
lim it u se fu ln ess
in c h ild re n .
D ro w sin ess,
ir rit a b ilit y a n d
vo m it in g m ay
b e s e en .
G iv e in d iv id ed
d ose s w it h
m ea ls a n d a t
b ed tim e t o
m in im iz e s id e
effe cts .
M eta b oliz e d b y
C YPs 1 A2 , 2 C 19
an d 3 A4 .
Im ip ra m in e 1 0 t o 2 5 m g In cre a se d aily
d ose b y 2 5 m g
aft e r a m in im um
of 7 d ays, if
n eed ed ; g iv e in
d iv id ed d ose s
w it h m ea ls a n d
bed tim e
10 t o 3 00 m g ( 2
to 6 m g/k g p er
d ay); d ose s > 2.5
m g/k g p er d ay
sh ou ld b e u se d
ca u tio u sly
B en zo d iaz ep in es
C lo n aze p am 0 .2 5 t o 0 .5 m g 1 t o 6 m g Ap plie s t o
c lo n aze p am a n d
lo ra ze p am :
Dro w sin ess,
ir rit a b ilit y a n d
op posit io n al
b eh avio r m ay
b e s e en
Su bje ct t o
a b u se ,
a d dic tio n a n d
div e rs io n
Lo ra ze p am 0 .2 5 t o 0 .5 m g 0.2 5 t o 8 m g
Clin ic ia n s s h ou ld b e a w are o f t h e p ote n tia l fo r a ctiv a tin g s id e e ffe cts o f a n tid ep re ssa n ts in y o u nger
ch ild re n a n d r e g u la to ry w arn in gs o f p ote n tia l fo r a n in cre a se d r is k o f s u ic id alit y in c h ild re n . Wi th
th e e xce p tio n o f d u lo xe tin e, a n tid ep re ssa n ts a re n ot a p pro ve d b y t h e U S F o od & D ru g
A dm in is tr a tio n fo r t r e a tm en t o f a n xie ty d is o rd ers in c h ild re n . R eco m men ded d ose s a re t h ose s h ow n
to h ave b een e ffe ctiv e in r a n dom iz e d c o n tr o ll e d t r ia ls o f c h ild re n w it h v a rio u s a n xie ty d is o rd ers a n d
clin ic a l e xp erie n ce . A ll d ose s s h ow n a re fo r o ra l a d m in is tr a tio n . O bse ssiv e -c o m pu ls iv e d is o rd er
(O CD ) is r e vie w ed s e p ara te ly in U pTo D ate .
EC G : e le ctr o ca rd io g ra m ; G I: g astr o in te stin al; G AD : g en era li z e d a n xie ty d is o rd er.
* C om mon g en era lly m ild a d ve rs e e ffe cts o f S S R Is a n d SN RIs s e en in c h il d re n t r e a te d fo r a n xie ty
d is o rd ers m ay in clu de h ea d ach e, a n ore xia , v o m it in g, s le ep d is tu rb an ce a n d s o m nole n ce .
¶ D ose - r e la te d E C G c h an ges h ave b een r e p orte d in c h il d re n a n d c lo se m on it o rin g is n ece ssa ry w it h la rg er
d ose s. Ac co rd in g t o t h e p ro d u ct in fo rm atio n a p pro ve d in t h e U nit e d St ate s, d ose s > 2.5 m g/k g p er d ay a re
n ot r e co m men ded in c h ild re n .
C ou rte sy o f a u th ors w it h a d dit io n al d ata fr o m :
1. K atz m an M A, B le a u P , B lie r P , e t a l. C an ad ia n c lin ic a l p ra ctic e g u id elin es fo r t h e m an ag em en t o f
an xie ty , p osttr a u m atic s tr e ss a n d o b se ssiv e -c o m pu ls iv e d is o rd ers . B M C P sy ch ia tr y 2 014; 1 4 Su ppl
1 :S1 .
2. R yn n M , P u lia fic o A , H ele n ia k C , e t a l. A dva n ce s in p h arm aco th era p y fo r p ed ia tr ic a n xie ty
d is o rd ers . D ep re ss A nxie ty 2 011; 2 8:7 6.
¶ ¶


3. M artin A , Sc ah ill L , K ra to ch vil C . P ed ia tr ic P sy ch op h arm aco lo g y, O xfo rd U niv e rs it y P re ss, N ew Y ork
2 010. p .4 80.
G ra p h ic 9 9025 V ers io n 3 .0

Contr ib uto r D iscl osu res
K im berly G la zie r L eo nte , P hD N oth in g to d is clo se A nth ony P ulia fic o , P hD N oth in g to
d is clo se P ete r N a, M D Noth in g to d is clo se M oir a A R yn n, M D Gra nt/R ese arc h /C lin ical T ria l
Support: S hire [A nxie ty ( G uanfa cin e)]; N IM H [A nxie ty ( M inocyclin e)]. D avid B re n t,
M D Gra nt/R ese arc h /C lin ical T ria l S upport: N IM H [C hild & A dole sce nt P sych ia tr y ]; A FS P
[S uic id e p re ve ntio n]. C onsu lta nt/A dvis ory B oard s: H ealth w ise [C onsu m er h ealth e duca tio n
(C hild P sych ia tr y )]; K lin genste in T hird G enera tio n F oundatio n [P ostd octo ra l fe llo wsh ip s]. P ate nt
H old er: G uilf ord P re ss [P sych olo gy ( T re a tin g d epre sse d a nd s u ic id al a dole sce nts )]; E R T In c
[C lo ud p la tfo rm s o lu tio n ( C -S SR S)]. O th e r F in ancia l In te re st: G uilf ord P re ss [P sych olo gy
(T re atin g d epre sse d a nd s u ic id al a dole sc e nts )]; E R T In c [C lo ud p la tfo rm s o lu tio n ( C -
SSR S)]. R ic h ard H erm an n, M D Noth in g to d is clo se
C ontr ib uto r d is clo su re s a re r e vie wed fo r c o nflic ts o f in te re st b y th e e dito ria l g ro up. W hen fo und,
th ese a re a ddre sse d b y v e ttin g th ro ugh a m ulti- le ve l re vie w p ro ce ss, a nd th ro ugh r e quire m ents
fo r r e fe re nce s to b e p ro vid ed to s u pport th e c o nte nt. A ppro pria te ly r e fe re nce d c o nte nt is
r e quire d o f a ll auth ors a nd m ust c o nfo rm to U pTo D ate s ta ndard s o f e vid ence .
C onflic t o f in te re st p olic y
X