Pengganti Jurnal (Bahasa Inggris)

8/16/2019 Pengganti Jurnal (Bahasa Inggris)

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Management of Acute Manic and Mixed Episodes in Bipolar Disorders

Terence A. Ketter, M.D.

Po W. Wang, M.D.

Over a period of 24 years, the U.S. ood and Dr!g Ad"in#istration $DA% approved thefirst three agents for "onotherapy treat"ent of ac!te "ania&'ithi!" in ()*+, ch'orpro"aine in

()*-, and diva'proe $a pro#prietary for"!'ation ofva'proate% in ())4 $Ta/'e 0#(%. or "!ch of

the ()*+sand ()1+s, 'ithi!" and first#generation antipsychotics ere the "ain treat#"ents for

ac!te "ania, /!t this changed as the efficacy 'i"itations of 'ithi!" and to'era/i'ity 'i"itations of

first#generation antipsychotics /eca"e "ore ev#ident, and ne treat"ent options e"erged. 3y

the 'ate ())+s, diva'proe had overtaen 'ithi!", and in the 2+++s, second#generation

antipsychotics overtoo first#generation antipsychotics. Th!s, since 2+++, five second#generation

anti#psychotics $o'anapine, risperidone, 5!etiapine, iprasidone, and aripiprao'e% have received

"onotherapy indications for ac!te "ania, and fo!r $o'anapine, risperidone, 5!etiapine, and

aripiprao'e% received ad6!nctive indications for ac!te "ania. 7n 2++4 a proprietary /eaded,

etended#re'ease caps!'e for"!'a#tion of car/a"aepine, and in 2++8 an etended#re'ease

for"!'ation of diva'#proe $diva'proe 9:%, received a "onotherapy indication for ac!te "ania.

7n

Table 6-1. Evidence-based treatment of acute manic and mixed episodes

Manic episodes Mied episodes With or

itho!t

Agitation associated

ith /ipo'ar disorder

Mood sta/i'iers;ithi!"- ()*+ # <

Diva'proea ())4 <

Diva'proe etended#re'ease 2++8 2++8 2++8

=ar/a"aepine etended#re'ease 2++4 2++4

Typica' antipsychotics

=h'orpro"ainea ()*->a'operido' < < <

Atypica' antipsychotics

O'anapinea 2+++,2++- / 2+++,2++- / < 2++4:isperidonea 2++-,2++- / 2++-,2++- / <

?!etiapinea 2++4 /,c <?!etiapine etended#re'ease 2++1 /,c 2++1 /,c <@iprasidonea 2++4 2++4 2++4 d

Aripiprao'ea 2++4, / 2++1 / 2++4,2++1 / 2++4 2++0Asenapine < <

ote. Dates signify year of initia' approva' in the United States.


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the approved agents, the first#generation antipsychotic ha'operido' and the second#generation

antipsychotic asenapine have "!'ticenter, rando"ied, do!/'e#/'ind, p'ace/o# and active#

co"parator#contro''ed dinica' tria's s!pporting their !se in ac!te "ania.

The DA#approved treat"ents are genera''y s!pported /y at 'east to "!'#ticenter, rando"ied,

do!/'e#/'ind, p'ace/o#contro''ed c'inica' tria's. 7n "ost instances, these are -#ee inpatientst!dies of "onotherapy in patients ith very 'i"ited psychiatric and "edica' co"or/idities. 7n

these tria's, in aggregate, the previo!s'y "entioned agents ith DA indications for the

"onotherapy treat"ent of ac!te "ania have yie'ded response $at 'east 8+F i"prove"ent in

"ania ratings% rates of approi"ate'y 8+F, as co"pared ith approi"ate'y -+F ith p'ace/o,

th!s representing a/o!t a 2+F increase in response rate $ig!re 0#(, 'eft side%. Patients receiving

either active treat"ent or p'ace/o a'so received additiona' s!/stantia' psychosocia' $ac!te

psychiatric hospita'iation%. and "odest phar"acotherapy $as#needed /enodiaepine for

approi"ate'y ( ee% interventions, acco!nting for a portion of /oth the active dr!g and the

p'ace/o responses. Si"i'ar'y, in aggregate, the response rates for to#dr!g co"# /ination therapy

$ith o'anapine, risperidone, 5!etiapine, or aripiprao'e added to 'ithi!" or diva'proe%

eceeded those for "onotherapy $ith 'ithi!" or diva'proe% /y a'"ost 2+F $ig!re 0#(, right

side%.

Treatment of Acute Mania: Balancing Benefits and is!s

=o"parisons s!ggest that "onotherapy response rates are "ore si"i'ar than different across

individ!a' approved agents and across "ood sta/i'iers co"# pared ith atypica' antipsychotics

$ig!re 0#2%. >oever, as noted ear'ier, so"e

"igure 6-1. #ver$ie%of 1&acute mania studies' %it( pooled response rates and numbersneeded to treat )**Ts+ for response.

Poo'ed data fro" (4 recent "onotherapy G'eftC see ig!re 0#2 'egend for dtations% and 4 recent

co"/ination $second#generation antipsychotic HSIAJ p'!s'ithi!" H;i ordiva'proe HDLPEJ%

therapy $rightC Sachs et a'. 2++2C Tohen et a'. 2++2/C Lieta et a'. 2++1aC atha" et a'. 2++4% ac!te

"ania st!dies. Monotherapy yie'ded approi"ate'y a 2(F increase in poo'ed response rate co"#

pared ith p'ace/o $approi"ate'y 8(F vs. -+F%. Active dr!g and p'ace/o rates are in part re#

'ated to /oth gro!ps a'so having ac!te hospita'iation and a fe days of resc!e /enodiaepine.

Monotherapy co"pared ith p'ace/o had an T for response of 8 $i.e., (++N2(.8B4.*&8,

ro!nded !p%. =o"/ination therapy yie'ded a/o!t a 2+F increase in poo'ed response rate co"#

pared ith "onotherapy $approi"ate'y 02F vs. 44F% and an T for response of0 $i.e., (++N

(1.-B8.8&0, ro!nded !p%. =3@Bcar/a"aepine.

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differences are seen in the esta/'ished efficacy profi'es of the approved agents $Ta/'e 0#(%.

everthe'ess, adverse effect differences a"ong individ!a' agentsappear to /e "ore noteorthy

and are noted 'ater in this chapter and descri/ed in detai' in =hapter (-, QMood Sta/i'iers and

Antipsychoticsand =hapter (4, QAntidepressants, Anio'yticsN>ypnotics, and Other

Medications,R of this hand/oo.

7n addition to data regarding "ood sta/i'iers and atypica' antipsychotics, there have /een

"!'tip'e contro''ed tria's of other anticonv!'sants in ac!te "a#

niaC hoever, as disc!ssed 'ater in this chapter, to date, on'y divaproe and car#/a"aepine and

possi/'y ocar/aepine appear effective.

7n this chapter, e revie the treat"ent of ac!te "ania, e"phasiing find#ings of recent

contro''ed st!dies. S!ch or is he'ping !s to refine o!r no'edge a/o!t 'ithi!", diva'proe,

and car/a"aepineC to appreciate the !ti'ity of sec#ond#generation antipsychoticsC and to

!nderstand the 'i"itations of other anti#conv!'sants in ac!te "ania. Th!s, in addition to the "oodsta/i'iers 'ithi!", diva'proe, and car/a"aepine, e consider to "ain categories of potentia'

ne treat"ent options for ac!te "ania second#generation antipsychotics and other

anticonv!'sants. Second#generation antipsychotics genera''y appear effective for ac!te "ania

$Ta/'e 0#(%. 7n contrast, other anticonv!'sants appear to have diverse psychotropic profi'es, and

a'tho!gh $ith the possi/'e eception of ocar/aepine% they are not effective for ac!te "ania,

they "ay have !ti'ity for other aspects of /ipo'ar disorders or co"or/id conditions.

A "our-Tier Approac(

7nterventions for the treat"ent of ac!te "ania are revieed !sing the fo!r#tier syste" presented

in Ta/'e 0#2. This syste" is a hy/rid approach, co"/ining ev# idence#/ased "edica' infor"ation

a/o!t efficacy and to'era/i'ity ith "ore e"pirica' constr!cts s!ch as fa"i'iarity and patient

accepta/i'ity to prioritie treat"ents in a fashion /road'y consistent ith orth A"erican c'inica'

prac# tice and treat"ent g!ide'ines.

Tier 7 treat"ent options have DA approva' for ac!te "ania and are s!p# ported /y the "ost

co"pe''ing evidence of efficacy. >oever, to'era/i'ity 'i"i# tations $partic!'ar'y in the 'onger

ter"% of at 'east so"e Tier 7 treat"ents "ay 'ead c'inicians and patients, after co"paring the

riss and /enefits, to con#sider other treat"ents.

The Tier 77 treat"ent option $asenapine% 'acs DA approva' for the treat#"ent of ac!te "ania /!t has co"pe''ing evidence of efficacy and to'era/i'ity advantages that "ight "ae it attractive

for a s!/stantia' n!"/er of patients once it receives approva'.

Tier 777 treat"ent options in "ost instances 'ac DA approva' for the treat# "ent of ac!te "ania

and have s!/stantive to'era/i'ity $i.e side effect% 'i"ita#tions andNor 'ess co"pe''ing evidence of

efficacy than do Tier 7 or 77 options. 7n genera', treat"ent g!ide'ines do not consider these

"oda'ities to /e first#'ine interventions /!t cite the" as inter"ediate priority options. >oever,

so"e Tier 777 options have "itigating advantages that "ight "ae the" attractive

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Poo'ed data fro" controUed tria's of the "ood sta/i'iers 'ithi!" $3oden et a'. ())4,2++8%, diva'proe $3oden et a', ())4,2++0%, and car/a"aepine $Weis'er et a'. 2++4a,

2++8% and the second#generation antipsychoticso'anapine $Tohen et a'. ())),2+++%, risperidone $>irschfe'd et a'. 2++4C Khannaet a'. 2++8%, 5!etiapine $3oden et a'. 2++8C

Mc'ntyre et a'. 2++8%, iprasidone $Kec et a'. 2++-/C Potin et a'. 2++8%, and aripiprao'e $Kec et a'. 2++-aC Sachs et a'. 2++0%, as e'' as p'ace/o $3oden et a'.

())4,2++8,2++0C >irschfe'd et a'. 2++4C Kec et a'. 2++-a, 2++-/C Khanna et a'. 2++8C Mc'ntyre et a'. 2++8C Potin et a'. 2++8C Sachs et a'. 2++0C Tohen et a'. ())),2+++C Weis'er

et a'. 2++4a, 2++8%. Ts for response for individ!a' agents ranged fro" 4 to *, re'ated to differences in response rates for active dr!gs and p'ace/o across st!dies. Poo'ed st!dies

of "ood sta/i'ier "onotherapies co"pared ith p'ace/o yie'ded response rates of approi"ate'y 8+F and 21F, respective'y, and a poo'ed T for response of 8 $(++N22.-B4.8

&8, ro!nded !p%. Poo'ed st!dies of second#generation antipsychotics and p'ace/o yie'ded response rates of approi"ate'y 8(F and -8F, respective'y, and an T for re#sponse

of * $(++N(0.-B0.( &*, ro!nded !p%. Th!s, a so"ehat higher poo'ed p'ace/o response rate in st!dies of second#generation antipsychotics co"pared ith "ood sta/i'iers

yie'ded a so"ehat higher poo'ed T for response for the for"er, despite si"i'ar response rates for active dr!gs. Aside fro" 'ithi!", >s for sedation are co"para/'e to Ts

for response, ref'ecting the sedative actions of approved treat"ents hen dosed ag# gressive'y as in ac!te "ania. =ontet of effects is cr!cia'&sedation of etre"e'y agitated

patients ear'y in the treat"ent of ac!te "ania "ay not yie'd prohi/itive pro/'e"s /!t "ay /eco"e increasing'y !naccepta/'e as "ania reso'ves and discharge approaches.

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Table 6-,. "our-tier approac( to t(e management of acute mania

Tier riorit *ame Treatment #ptions

7 >igh Approved Mood sta/i'iers 'ithi!", diva'proe

Second#generation antipsychotics

o'anapine, risperidone, 5!etiapine,,iprasidone, aripiprao'e

77 >igh >igh#priority

!napproved

Other second#generation

antipsychotics asenapine

777 7nter"ediate Other Other "ood sta/i'iers

car/a"aepine

irst#generation antipsychotics

ch'orpro"aine, thioridaine,

thiothiene, pi"oide, ha'operido'

Other second#generation

antipsychotics c'oapineAd6!nctive /enodiaepines

9'ectroconv!'sive therapy

7L ;o ove' Ad6!ncts Other "ood sta/i'iers 'a"otriginea

Other anticonv!'sants ocar/aepine,

ga/apentin,a topira"ate, a tiaga/ine, /

'evetiraceta", / onisa"ide/ a

Ad6!nctive psychotherapy

a7neffective in contro''ed ac!te "ania tria's. / ot assessed in contro''ed ac!te "ania tria's, as of ear'y 2++).

for se'ected patients, and in certain circ!"stances, so"e of these interventions "ay /e

considered ear'y on $e.g., e'ectroconv!'sive therapy H9=TJ in pregnant o"en%.

Tier 7L treat"ent options 'ac DA approva' for the treat"ent of ac!te "ania and have even"ore 'i"ited evidence of efficacy than do Tier 7, 77, or 777 options. 7ndeed, so"e of theseinterventions have /een proven to /e ineffective in ac!te "ania /!t "ay have !ti'ity for co"or/id conditions. 7n genera', treat"ent g!ide'ines consider these "oda'ities to /e 'o# priority interventions.

Tier /: Approved Acute Mania Treatment

#ptions for Bipolar DisorderThe approved ac!te "ania treat"ents inc'!de three "ood sta/i'iers $'ithi!", diva'proe, andcar/a"aepine%, five second#generation antipsychotics $o'an#apine, risperidone, 5!etiapine,

iprasidone, and aripiprao'e%, and the first# generation antipsychotic ch'orpro"aine. 3eca!se

of co"p'eity of !se and to'era/i'ity 'i"itations, car/a"aepine and ch'orpro"aine are assignedto Tier 777. As noted ear'ier and descri/ed in greater detai' in this section, Tier 7 options have

favora/'e efficacy $sing'e#digit TsC ig!re 0#2%, a'tho!gh so"e a'so "ay have safety or

to'era/i'ity cha''enges. Th!s, to'era/i'ity 'i"itations of so"e Tier 7 treat"ents "ay 'ead

c'inicians and patients, after co"paring the riss and /enefits, to consider other treat"ents.

Mood 0tabiliers

Mood sta/i'iers are considered fo!ndationa' treat"ents for /ipo'ar disorders, and threeof theseagents $'ithi!", diva'proe, and car/a"aepine% have indi# cations for the treat"ent of ac!te

"ania. The first#'ine ac!te "ania treat"ent options&'ithi!" and diva'proe&are disc!ssed in

this section, hereas the a'ternative treat"ent car/a"aepine is disc!ssed in the section on Tier

777 treat"ents. The other "ood sta/i'ier, 'a"otrigine, as disc!ssed in the section on

Tier 7L treat"ents, is ineffective in ac!te "ania.

/it(iiini.

;ithi!" as first reported to have efficacy in ac!te "ania /y ohn =ade $()4)%, as ide'y !sed

for the treat"ent of "ania in 9!rope in the ()0+s, and received DA approva' as "onotherapyfor "anic episodes of "anic# depressive i''ness in ()*+ and as "aintenance therapy to prevent or

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di"inish the intensity of s!/se5!ent episodes in those "anic#depressive patients ith a

history of "ania in ()*4. 7n the ()*+s and ()1+s, 'ithi!" and first#generation an# tipsychotics

ere the pri"ary agents !sed in the treat"ent of "ania. As noted in =hapter (+ of this vo'!"e,

QManage"ent of 3ipo'ar Disorders in =hi'dren and Ado'escents,R 'ithi!" as the first agent

approved for the treat"ent of "ania in ado'escents $age (2 years and o'der%. >oever, ith the

e"ergence of diva'proe and atypica' antipsychotics, this changed dra"atica''y in the 'ate ())+s

and ear'y 2+++s. >oever, 'ithi!" contin!ed to /e co""on'y !sed, partic!'ar'y in

co"/ination ith other agents. 7ndeed, /eteen 2++- and 2++1, fo!r second# generation

antipsychotics $o'anapine, risperidone, 5!etiapine, and aripipra#o'e% ere approved for !se in

co"/ination ith 'ithi!" $or diva'proe% for ac!te "ania.

9ar'y p'ace/o#contro''ed st!dies of 'ithi!" in ac!te "ania had rando"ied $Maggs ()0-C Scho!

et a'. ()84% and nonrando"ied $Ioodin et a; ()0)C Stoes et a'. ()*(% crossover designs.

Despite "ethodo'ogica' differences and 'i"itations, these st!dies consistent'y fo!nd that

approi"ate'y 1+F of the patients ith ac!te "ania responded to 'ithi!" $Ioodin and @is

()*)%.

7ndivid!a' ear'y st!dies fo!nd that 'ithi!" co"pared ith first#generation antipsychotics tended

to have co"para/'e overa'' efficacy, ith advantages 'ater in treat"ent ith 'ithi!" for

achieving re"ission of the f!'' "anic syndro"e s!fficient to per"it discharge /!t disadvantages

ear'y in treat"ent ith 'ithi!" ith respect to rapid contro' of agitation in high'y active patients

$Iarfine' eta'. ()1+C ohnson et a'. ()01,()*(C Prien et a'. ()*2C Shopsin et a'. ()*8%. >o#

ever, a "eta#ana'ysis of five contro''ed ac!te "ania tria's $ohnson et a'. ()01,()*(C Shopsin et

a'. ()*8C Spring et a'. ()*+C Taahashi et a'. ()*8% fo!nd the poo'ed response rate ith 'ithi!"

$1)F% s!perior to that ith ne!ro'eptics $-1F% $ani#ca et a'. ())2%. 7n so"e st!dies, co"/ining

first#generation antipsychotics ith 'ithi!" appeared to yie'd enhanced therape!tic effects

$Iarfine' et a'. ()1+CS"a'' et a', ))8%.

With ti"e,it /eca"e evident that a'tho!gh 'ithi!" provided i"pressive /enefits in c'assic $p!re%

"ania, it had s!/stantia' efficacy U"itations in "ied episodes $ree"an et a'. ())2C Ke''er et

a'. ()10C Sec!nda et a'. ()18%, dysphoric "ania $Sann et a'. 2++2%, secondary "ania

$Kra!tha""er and K'er"an ()*1%,and rapid#cyc'ing /ipo'ar disorder $K!op!'os et a'. ()1+%.

=onte"porary "!'ticenter, rando"ied do!/'e#/'ind, p'ace/o#contro''ed tria's of other

"edications, in hich 'ithi!" as an active co"parator, have confir"ed 'ithi!"Vs efficacy in

ac!te "ania $3oden et a'. ())4,2+++, 2++8C i!fan eta'. 2++1%, a'/eit at ti"es ith so"ehat'oer response rates than in ear'y st!dies.

:ando"ied do!/'e#/'ind, p'ace/o#contro''ed ac!te "ania st!dies have indicated efficacy hen

'ithi!" $or diva'proe% as a!g"ented ith o'ana#pine $Tohen et a'. 2++2/%, risperidone $Sachs

et a'. 2++2C atha" et a'. 2++-%, 5!etiapine $Sachs et a'. 2++4C atha" et a'. 2++4%, or

aripiprao'e $Lieta et a'. 2++1a%. 7n these st!dies, "ean ser!" 'ithi!" concentrations ranged

/eteen +.* and +.1 "95N;, and as descri/ed 'ater in this chapter $see s!/section QSec# ond#

Ieneration AntipsychoticsR%, addition of a second#generation antipsy# chotic tended to yie'd

"ore adverse effects. 7n vie of these co"/ination therapy st!dies, the 2++2 revision of the

A"erican Psychiatric Association $2++2% QPractice I!ide'ine for the Treat"ent of Patients With3ipo'ar DisorderR reco""ended co"/inations of antipsychotics and "ood sta/i'iers as first#

'ine interventions for the treat"ent of severe cases of ac!te "ania.

The U.S. prescri/ing infor"ation for 'ithi!" reco""ends targeting ser!" 'ithi!" concentrations

for ac!te "ania therapy of (.+&(#8 "95N;, hich !s!a''y are achieved ith divided dosages of

(,1++ "gNday. To 'i"it ear'y adverse effects, 'ithi!" for ac!te "ania is co""on'y introd!ced at

'oer $0++#)++ "gNday%

dosages and grad!aUy increased to higher dosages !nti' therape!tic efficacy is ade5!ate, adverse

effects s!pervene, or ser!" concentrations eceed (.2 "95N; dinicians and patients co""on'y

endeavor to have "ost of or, if possi/'e, the en tire'ithi!" dose taen at /edti"e to enhance

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convenience and to have pea 'ithi!" ser!" concentrations, and hence the "a6or /!rden of

adverse effects, d!ring s'eep. 9!thy"ic or depressed co"pared ith "anic patients tend to /e

7ess a/'e to to'erate adverse effects and th!s "ay re5!ire even "ore grad!a' initiation and

'oer fina' dosages. :esponse ith ade5!ate to'era/i'ity of 'ithi!" in ac!te "ania

tends to occ!r ith ser!" concentrations /eteen +.1 and (2 "95N;. Ser!" concentrations

greater than (.2 "95N; yie'd increasing'y pro/'e"atic adverse effects, so that dinica''y it is

!nco""on to eceed (.2 "95N;, despite (.8 "95N; /eing the reco""ended "ai"!" dosage

in the prescri/ing infor"ation.

;ithi!" 'i"itations inc'!de co""on adverse effects s!ch as tre"or, po'y# ! ria, and po'ydipsia

that can occ!r hen ser!" concentrations are ithin the therape!tic range $+.1#(.2 "95N;%.

7ncreasing'y pro/'e"atic diarrhea, vo"it# ing, drosiness, "!sc!'ar eaness, and

incoordination can occ!r ith higher 'eve's, and severe adverse effects invo'ving "!'tip'e organ

Syste"s e"erge at concentrations greater than 2.+ "95N;. ;ithi!" dosages 7ess than (,+++

"gNday are !s!a''y e'' to'erated, hereas dosages greater than 2,+++ "gNday co"#

"on'y yie'd side effects, /!t adverse effects are "ore c'ose'y re'ated to ser!" 'ithi!"

concentrations than to dosage. Th!s, the U.S. prescri/ing infor"ation inc'!des a /oed arning

that 'ithi!" toidty is c'ose'y re'ated to ser!" 'ith# i!" concentrations and can occ!r at doses

yie'ding dose to therape!tic ser!" concentrations. The prescri/ing infor"ation a'so inc'!des a

arning to avoid 'ithi!" in patients ith significant rena' or cardiovasc!'ar disease, severe de#

/i'itation or dehydration, or sodi!" dep'etion /eca!se the ris of 'ithi!" toicity is very high.

Other arnings in the prescri/ing infor"ation inc'!de the riss of rena' adverse effects, ind!ding

nephrogenic dia/etes insipid!s, riss of g'o"er!'ar and interstitia' fi/rosis ith chronic 'ithi!"

therapy, and reports of cases of encepha'opathic syndro"e $eanessC 'ethargyC feverC

tre"!'o!snessC conf!sionC etrapyra"ida' sy"pto"sC 'e!ocytosisC and e'evated ser!" en#y"es, ser!" !rea nitrogen, and fasting /'ood s!gar% fo''oed /y irreversi/'e /rain da"age

hen 'ithi!" as co"/ined ith ne!ro'eptics&"ost nota/'y, ha'operido'. This iss!e is

considered in greater detai' in the section on 'ithi!" in =hapter (- of this vo'!"e.

9tended#co"pared ith i""ediate#rdease 'ithi!" for"!'ations "ay at# ten!ate adverse effects

in genera' /y yie'ding 'oer pea ser!" concentrations and feer !pper gastrointestina' adverse

effects $na!sea and vo"iting% /y de'aying a/sorption /iit can eacer/ate 'oer gastrointestina'

pro/'e"s $s!ch as diarrhea% as a res!'t of de'ayed a/sorption. ;a/oratory "onitoring of not on'y

ser!" 'ithi!" concentrations /!t a'so thyroid and rena' f!riction is necessary /eca!se thyroid

and rena' adverse effects a'so can occ!r. As disc!ssed in =hapter (( of this vo'!"e,QManage"ent of 3ipo'ar Disorders in Wo"en,R 'ithi!" is a'so teratogenic $DA pregnancy

category D /eca!se of cardiac "a'for"ations in approi"ate'y (F%.

Physio'ogica' conditions, "edica' disorders, and dr!g interactions can in crease ser!" 'ithi!"

concentrations, potentiafiy yie'ding toidty. Th!s, ser!" 'ithi!" concentrations rise ith

dehydrationC sodi!" dep'etionC advanced ageC rena' diseaseC and conco"itant ad"inistration of

angiotensin#converting eny"e inhi/itors, "etronidao'e, thiaide di!retics, and nonsteroida'

anti#inf'a"# "atory dr!gs.

7n s!""ary, 'ithi!" is a traditiona' treat"ent for ac!te "ania. Despite 'ithi!"Vs to'era/i'ity

'i"itations and the e"ergence of "!'tip'e ne treat"ent options, 'ithi!" re"ains a fo!ndationa'

treat"ent for /ipo'ar disorder. As dis# c!ssed in =hapter 1 of this vo'!"e, Q;onger#Ter"

Manage"ent of 3ipo'ar Disorders,R 'ithi!" a'so has a 'onger#ter" /ipo'ar treat"ent indication

and is considered a high#priority "aintenance therapy /y "!'tip'e treat"ent g!ide#'ines. Th!s,

patients ith ac!te anti"anic responses a'so "ay /e good candidates for 'onger#ter" 'ithi!"

therapy.

Divalproex. The anticonv!'sant diva'proe has /een avai'a/'e for the treat"ent of epi'epsyin the

United States since ()*1. Diva'proe received DA approva' as "onotherapy for "anic episodes

associated ith /ipo'ar disorder in ())4 $3oden et a'. ())4%. 3y the 'ate ())+s, diva'proe had

overtaen 'ithi!" as the "ost co""on treat"ent for ac!te "ania, in part /eca!se of enhanced

7


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to'era# /i'ity and in part /eca!se of a /roader spectr!" of efficacy. 3eteen 2++- and 2++1, fo!r

second#generation antipsychotics $o'anapine, risperidone, 5!etia#pine, and aripiprao'e% ere

approved for !se in co"/ination ith diva'proe $or 'ithi!"% for ac!te "ania. 7n 2++8, a

diva'proe etended#re'ease for"!'ation $diva'proe 9:% received a "onotherapy indication for

the treat"ent of ac!te "anic and "ied episodes $3oden et a'. 2++0%.

Diva'proe appears to have a /roader spectr!" of efficacy than does 'ithi!", yie'ding /enefit in

patients ith histories of 'ithi!" fai'!re $3oden et a'.())4C Pope et a'. ())(% and 'ithi!"#

resistant i''ness s!/types, s!ch as patients ith dysphoric "anic $ree"an et a'. ())2C Sann et

a'. ())*% and "!'tip'e prior $Sann et a'. 2+++% episodes.

To "!'ticenter, rando"ied, do!/'e#/'ind, active#co"parator st!dies s!ggested that for

diva'proe co"pared ith o'anapine in ac! te "ania, diva'#proe had a "odest to'era/i'ity $'ess

sedation and eight gain% advantage and o'anapine had a s'ight efficacy advantage $Tohen et a'.

2++2aC @a6eca et a'. 2++2%.

:ando"ied, do!/'e#/'ind, p'ace/o#contro''ed ac!te "ania st!dies have indicated efficacy hen

diva'proe $or 'ithi!"% as a!g"ented ith o'ana# pine $Tohen et a'. 2++2/%, risperidone

$Sachs et a'. 2++2C atha" et a'. 2++-%, 5!etiapine $De'3e''o et a; 2++2C Sachs et a'. 2++4C

atha" et a'. 2++4%, aripipra#o'e $Lieta et a' 2++1a%. 7n these st!dies, "ean ser!" va'proate

concentrations ranged /eteen 04 and (+4 pgN";, and as descri/ed 'ater in this chapter $see

s!/section QSecond#Ieneration AntipsychoticsR%, addition of a second#gener# ation antipsychotic

tended to yie'd so"ehat "ore adverse effects.

7n another "!'ticenter, rando"ied, do!/'e#/'ind, p'ace/o#contro''ed st!dy, va'proate co"/ined

ith antipsychotics $pri"ari'y ha'operido' andNor peraine% as significant'y "ore effective than p'ace/o p'!s antipsychotics $M!''er#Oer'ingha!sen et a'. 2+++%. 7n this st!dy, cotherapy ith

va'proate as associated ith 'oer antipsychotic doses and as genera''y e'' to'erated, ith

asthenia as the on'y adverse effect "ore co""on ith co"/ination therapy and a 'o rate of

discontin!ation for adverse events $2.)F vs. -.+F ith "ono#therapy%.

7n vie of the co"/ination therapy st!dies descri/ed ear'ier in this section, the 2++2 revision of

the A"erican Psychiatric Association $2++2% QPractice I!ide# 'ine for the Treat"ent ofPatients

With 3ipo'ar DisorderR reco""ended co"/inations of antipsychotics and "ood sta/i'iers as

first#'ine interventions for the treat"ent of severe cases of ac!te "ania.

:ecent st!dies are he'ping to refine f!rther o!r no'edge of the dinica' !ti'ity of diva'proe in

/ipo'ar disorders. Th!s, diva'proe ora' 'oading $initi# ating at 2+#-+ "gNgNday for 2 days and

then 2+ "gNgNday% rapid'y yie'ded therape!tic $8+#(28 pgN";% /'ood concentrations and

appeared to /e rapid'y effective and e'' to'erated in ac!te "ania $>irschfe'd et a'. 2++-%.

A 'arge "!'ticenter, rando"ied, do!/'e#/'ind, p'ace/o#contro''ed -#ee tria' in patients ith

ac!te "anic episodes and "ied episodes, ith and ith# o!t psychosis, fo!nd diva'proe 9: to

/e effective ffo" day 8 onard $3oden et a'. 2++0%. Diva'proe 9: as ad"inistered once

dai'y in the "orning, starting at 28 "gNg, increasing /y 8++ "g on day -, and ad6!sting to

ser!" va'proate concentrations of18#(28 pgN";. Mean ser!" va'proate concentrations

greater than (+8 pgN"; ere associated ith "ore ffe5!ent gastrointestina' ad#

verse effects. The a!thors cond!ded that ser!" va'proate concentrations genera''y sho!'d not

eceed (++ $igN"; for "anic patients ith ade5!ate dinica' i"prove"ent. ='inica''y significant

eight gain $at 'east *F indrease% as "ore co""on ith diva'proe 9: $)F% than ith

p'ace/o $-F%. Diva'proe tends to /e so"ehat /etter to'erated than 'ithi!" or car/a#

"aepine, ith =entra' nervo!s syste" and gastrointestina' pro/'e"s /eing the "ost co""on

adverse effects. The prescri/ing infor"ation in the United States has /een revised to add rare

pancreatitis to the prior /oed a"ings ofter# atogenidty $DA pregnancy category D, d!e to

spina /ifida in approi"ate'y 'F#2F% and rare hepatotoicity. As noted in =hapter (( of this

vo'!"e, recent data s!ggest that rates of "a'for"ations ith diva'proe co!'d /e higher co"#

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pared ith rates ith 'a"otrigine or co"pared ith rates ith no anticonv!'sant epos!re

$A'sdorf et a; 2++4C =!nnington 2++4C La6da et a'. 2++4%. Other arn# ings in the prescri/ing

infor"ation inc'!de the riss of hypera""one"ic en# cepha'opathy in patients ith rare !rea

cyde disorders, increased so"no'ence in the e'der'y, and thro"/ocytopenia.

7n 2++1, the DA re'eased an a'ert regarding increased ris of s!icida'ity $s!icida' /ehavior or ideation% in patients ith epi'epsy and psychiatric dis# orders for (( anticonv!'sants $inc'!ding

diva'proe%. 7n the DAVs ana'ysis, anticonv!'sants co"pared ith p'ace/o yie'ded

approi"ate'y tice the ris of s!idda'ity $+.4-F vs +.22F%. The re'ative ris for s!icida'ity

as higher in the patients ith epi'epsy than in those ith psychiatric disorders.

As noted in =hapter (( ofthis vo'!"e, for "ore than a decade there have /een varying reports

regarding a possi/'e association /eteen va'proate therapy and po'ycystic ovary syndro"e in

o"en ith epi'epsy $7so6arvi et a; ())-C :asgon 2++4%. To recent st!dies in patients ith

/ipo'ar disorder reported the possi/i'ity of a 1F#'+F ris of po'ycystic ovary syndro"e in

o"en ith /i# po'ar disorder treated ith va'proate $offe et a' 2++0C :asgon et a'. 2++8% andhave indicated the need for prospective tria's to assess this iss!e syste"atica''y.

La'proate has so"e dr!g interactionsC it can inhi/it "eta/o'is" of other dr!gs, inc'!ding

'a"otrigine and the active car/a"aepine epoide "eta/o'ite. Moreover, va'proate is s!scepti/'e

to eny"e ind!cers, so that car/a"aepine decreases va'proate ser!" concentrations. Additiona'

infor"ation a/o!t va'#proate is provided in =hapter (- of this vo'!"e.

7n s!""ary, diva'proe is an i"portant treat"ent option for ac!te "ania that "ay have efficacy

and to'era/i'ity advantages over 'ithi!". As disc!ssed in =hapter 1 ofthis vo'!"e, a'tho!gh

'acing an DA 'onger#ter" treat"ent indication, diva'proe has s!fficient evidence of efficacyto /e considered a high#

priority "aintenance therapy /y "!'tip'e treat"ent g!ide'ines, so that patients ith ac!te

anti"anic responses a'so "ay /e good candidates for 'onger#ter" diva'proe therapy.

0econd-2eneration Antipsc(otics

7n ())4, the second#generation antipsychotic risperidone as approved for the treat"ent of

schiophrenia. 7n the 'ate ())+s and the ear'y 2+++s, second#generation antipsychotics overtoo

first#generation antipsychotics in treat"ent of schiophrenia and then ac!te "ania, pri"ari'y

/eca!se of to'era/i'ity concerns regarding the o'der agents and the i"pressive efficacy evidence /ase acc!"!'ated for the neer dr!gs. The !se of second#generation antipsychotics in "a#

nia is descri/ed in the fo''oing s!/sections, ith additiona' infor"ation a/o!t neer

antipsychotics provided in =hapter (- of this vo'!"e.

O'anapine. O'anapine received DA approva' for the treat"ent of schio#phrenia in ())*, for

ac!te "anic or "ied episodes associated ith /ipo'ar dis#order as "onotherapy in ad!'ts in

2+++, and as co"/ination therapy $ith 'ithi!" or va'proate% in ad!'ts in 2++-. Despite

contro''ed evidence of efficacy as "onotherapy for ac!te "anic or "ied episodes associated

ith /ipo'ar dis#order in ado'escents ages(-&(* years $Tohen et a'. 2++*%, this !se has notyet

/een approved /y the DA. This iss!e is disc!ssed in =hapter (+ of this vo'!"e. A rapid#actingintra"!sc!'ar for"!'ation of o'anapine as indicated for the treat"ent of agitation

associated ith schiophrenia and /ipo'ar 7 "ania in ad!'ts in 2++4.

=ontro''ed tria's a'so indicated that o'anapine had!ti'ity in other phases of /ipo'ar disorders. As

noted in =hapter 1 of this vo'!"e, o'anapine received an indication for 'onger#ter"

"onotherapy for /ipo'ar disorder in 2++4. A'so, as descri/ed in =hapter * of this vo'!"e,

QManage"ent of Ac!te Ma6or Depressive 9pisodes in 3ipo'ar Disorders,R in 'ate 2++-, the

co"/ination of o'anapine ith f'!oetine /eca"e the first treat"ent approved for ac!te /ipo'ar

depression.

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S!/stantia' evidence s!pports the efficacy of o'anapine in ac!te "anic and "ied episodes.

M!'ticenter, rando"ied, do!/'e#/'ind, p'ace/o#contro''ed tri# a's indicate that o'anapine is

effective in ac!te "anic and "ied episodes /oth as "onotherapy $7/hen et a; ())),2+++% and

as ad6!nctive treat"ent $added to 'ithi!" or va'proate% $Tohen et a'. 2++2/%.

As noted ear'ier, to "!'ticenter, rando"ied, do!/'e#/'ind, active# co"parator tria's s!ggestedthat in ac!te "anic and "ied episodes, o'ana# pine co"pared ith divaproe as s'ight'y

"ore effective /!t had s'ight'y "ore

adverse effects $Tohen et a'. 2++2aC @a6eca et a'. 2++2%. O'anapine a'so has /een assessed in

head#to#head co"parisons ith 'ithi!" and ha'operido' in ac!te "ania. =o"pared ith 'ithi!",

o'anapine as so"ehat "ore effective /!t yie'ded "ore eight gain $i!fan et a'. 2++1%.

O'anapine co"pared ith ha'operido' yie'ded si"i'ar efficacy and feer etrapyra"ida'

adverse effects /!t "ore eight gain $Tohen et a'. 2++-%.

A'so, a "!'ticenter, rando"ied, do!/'e#/'ind, active#co"parator tria' s!g# gested that ininpatients ith ac!te "anic and "ied episodes, o'anapine co"pared ith risperidone had

si"i'ar anti"anic efficacy /!t an advantage ith respect to depressive sy"pto"s and so"ehat

different adverse effects $Per'is et a'. 2++0%. O'anapine co"pared ith risperidone yie'ded

significant'y "ore eight gain /!t significant'y 'ess hyperpro'actine"ia and se!a' dysf!nction.

Ad6!nctive o'anapine $added to 'ithi!" or diva'proe% as effective in ac!te "ania tria's and

as approved /y the DA for this indication. >oever, ith co"/ination therapy co"pared ith

"onotherapy, the efficacy /enefit as acco"panied /y to'era/i'ity 'i"itations s!ch as

so"no'ence, dry "o!th, tre"or, and s'!rred speechC increased appetiteC eight gainC and

discontin!ation /eca!se of adverse events.

7n contrast, ad6!nctive o'anapine $added to car/a"aepine% as no /etter than ad6!nctive

p'ace/o added to car/a"aepine in patients ith "anic and "ied episodes /!t yie'ded "ore

eight gain and higher ser!" trig'yceride concentrations $Tohen et a'. 2++1%.

O'anapine is avai'a/'e in an intra"!sc!'ar for"!'ation that is indicated for the treat"ent of

agitation associated ith schiophrenia and /ipo'ar 7 "ania in ad!'ts $Meehan et a'. 2++(%.

7n ac!te "anic and "ied episodes in ad!'ts, ora' o'anapine as "onotherapy is started at (+#(8

"g once dai'y and titrated as high as 2+ "gNdayC hen co"/ined ith 'ithi!" or diva'proe,

o'anapine is started at (+ "g once dai'y and titrated to 8#2+ "gNday. The reco""endedintra"!sc!'ar o'anapine dose is (+ "g $'oer doses "ay /e considered as c'inica''y indicated%

and, as necessary and to'erated, can /e repeated after 2 ho!rs, and repeated again after 4 "ore

ho!rs, for a "ai"!" dosage of -+ "gNday. The "ost co""on adverse effects ith ora'

o'anapine are so"no'ence, dry "o!th, diiness, asthenia, constipation, dyspepsia, increased

appetite, and tre"or. So"no'ence is the "ost co""on adverse effect ith intra"!sc!'ar

o'anapine. Mai"a' dosing of intra#"!sc!'ar o'anapine "ay yie'd s!/stantia' orthostatic

hypotension, so that ad"inistration of additiona' doses to patients ith c'inica''y significant pos#

t!ra' changes in systo'ic /'ood press!re is not reco""ended.

The U.S. prescri/ing infor"ation for o'anapine inc'!des a /oed arning regarding theincreased ris of "orta'ity $pri"ari'y cardiovasc!'ar or infectio!s% in e'der'y patients ith

de"entia#re'ated psychosis $an antipsychotic c'ass arning%. The DA has stip!'ated changes in

the o'anapine U.S. prescri/ing infor"ation to ref'ect the ris of hyperg'yce"ia and dia/etes

"e''it!s, and the report of a recent consens!s deve'op"ent conference s!ggested that the riss

of o/esity, dia/etes, and hyper'ipide"ia ith this agent $and c'oapine% are greater than ith

other second#generation antipsychotics $PhysiciansV Des :eference 2++1%. Th!s, c'inica' and $as

indicated% 'a/oratory "onitoring for o/esity, dia/etes, and hyper'ipide"ia appears pr!dent for

patients receiving o'anapine. Other arnings in the prescri/ing infor"ation inc'!de the riss of

cere/rovasc!'ar adverse events, inc'!ding stroe, in e'der'y patients ith de# "entiaC ne!ro'eptic

10


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"a'ignant syndro"eC and tardive dysinesia. To date, o'an# apine has not /een associated ith

congenita' "a'for"ations in h!"ans $DA pregnancy category =%.

O'anapine has so"e dr!g#dr!g interactions /eca!se certain eny"e in# d!cers s!ch as

car/a"aepine and to/acco s"oing can decrease ser!" o'an# apine concentrations. 7ndeed, in

a co"/ination therapy st!dy, car/a"aepine yie'ded 'oer than epected /'ood o'anapineconcentrations, and even tho!gh this as addressed in part /y "ore aggressive o'anapine

dosing, the efficacy of the o'anapine p'!s car/a"aepine co"/ination as sti'' not significandy

/etter than that of car/a"aepine "onotherapy in the treat"ent of ac!te "ania

$Tohen et a'. 2++1%. A'so, to/acco s"oing as associated ith poorer o'ana# pine response in a

post hoc ana'ysis of three o'anapine ac!te "ania st!dies $3er et a'. 2++1%. 7n contrast, so"e

eny"e inhi/itorss!ch asf'!voa"ine "ay increase ser!" o'anapine concentrations. =oncerns

have /een raised regarding the riss of ecessive sedation and cardiorespiratory depression ith

conco"itant ad"inistration of intra"!sc!'ar o'anapine and /enodiaepines.

7n s!""ary, o'anapine, as /oth "onotherapy and ad6!nctive therapy, is effective for ac!te"ania. Moreover, o'anapine has a 'onger#ter" /ipo'ar treat# "ent indication, so that patients

ith ac!te anti"anic responses a'so "ay /e good candidates for 'onger#ter" o'anapine therapy.

>oever, sedation, eight gain, and "eta/o'ic pro/'e"s "ay 'i"it the !ti'ity of this agent,

partic!'ar'y in 'onger#ter" treat"ent.

:isperidone. :isperidone received DA approva' for the treat"ent of schio# phrenia in ())4,

for ac!te "anic or "ied episodes associated ith /ipo'ar 7 disorder in ad!'ts as "onotherapy as

e'' as in co"/ination ith 'ithi!" or

va'proate in 2++-, and for ac!te "anic or "ied episodes associated ith /ipo'ar 7 disorder as"onotherapy in chi'dren and ado'escents ages (+#(* years in 2++* $PhysiciansV Des :eference

2++1C httpNN.fda.govN//sNtopicsN9WSN 2++*N9W+(010.ht"'%. The 'atter is descri/ed in

=hapter (+ ofthis vo'!"e. :isperidone a'so received an indication for irrita/i'ity and /ehavior

pro/'e"s associated ith a!tistic disorder in chi'dren and ado'escents ages 8&(0 years in

2++0 $Mc=racen et a'. 2++2%. A 'ong#acting in6ecta/'e for"!'ation of risperi# done as

approved for the treat"ent of schiophrenia $/!t not /ipo'ar disorder as of ear'y 2++)% in 2++-.

The active "eta/o'ite of risperidone $pa'iperidone% as approved for the treat"ent of

schiophrenia $/!t not /ipo'ar disorder as of ear'y 2++)% in 2++0.

M!'ticenter, do!/'e#/'ind, p'ace/o#contro''ed tria's esta/'ished the efficacy of risperidone"onotherapy in ac!te "ania $>irschfe'd et a'. 2++4C Khanna et a'. 2++8%.

As noted ear'ier in this chapter, a "!'ticenter, rando"ied, do!/'e#/'ind, active#co"parator tria'

s!ggested that in inpatients ith ac!te "anic and "ied episodes, o'anapine co"pared ith

risperidone had si"i'ar anti"anic efficacy /!t an advantage ith respect to depressive sy"pto"s

and so"ehat different adverse effects $Per'is et a'. 2++0%.

7n addition, to "!'ticenter, rando"ied, do!/'e#/'ind, p'ace/o#contro''ed st!dies confir"ed the

efficacy of ad6!nctive $added to 'ithi!" or diva'proe% risperidone in ac!te "ania $Sachs et a'.

2++2C atha" et a'. 2++-%.

7n ac!te "ania in ad!'ts, risperidone is started at 2#- "g once dai'y and ad# 6!sted /y ( "gNday

as necessary and to'erated, ithin a range of (#0 "gNday. The "ost co""on risperidone adverse

effects ith "onotherapy are so"no'ence, dystonia, aathisia, dyspepsia, na!sea, parinsonis",

/'!rred vision, and in# creased sa'ivation and ith ad6!nctive therapy are so"no'ence, diiness,

parinsonis", increased sa'ivation, aathisia, a/do"ina' pain, and !rinary in# continence.

:isperidone a'so ca!ses hyperpro'actine"ia, so assess"ent of se# r!" pro'actin "ay prove

!sef!' in patients ho have "enstr!a' irreg!'arities, ga'actorrhea, or diffic!'ties ith se!a'

desire and fi"ction.

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The U.S. prescri/ing infor"ation for risperidone inc'!des a /oed arning regarding the

increased ris of "orta'ity $pri"ari'y cardiovasc!'ar or infectio!s% in e'der'y patients ith

de"entia#re'ated psychosis $an antipsychotic c'ass arning%. The DA has stip!'ated changes in

the risperidone U.S. prescri/ing infor"ation to ref'ect the riss of hyperg'yce"ia and dia/etes

"e''it!s, and the report of a recent consens!s deve'op"ent conference s!ggested that the riss of

o/esity, dia/etes, and hyper'ipide"ia ith this agent are inter"ediate, /eing

'ess than ith c'oapine and o'anapine /!t "ore than ith iprasidone and aripiprao'e

$PhysiciansV Des :eference 2++1%. Th!s, c'inica' and $as indicated% 'a/oratory "onitoring for

o/esity, dia/etes, and hyper'ipide"ia appears pr!dent for patients receiving risperidone. Other

arnif'gs in the prescri/ing infor"ation inc'!de the riss ofcere/rovasc!'ar adverse events,

inc'!ding stroe, in e'der'y patients ith de"entiaC ne!ro'eptic "a'ignant syndro"eC and tardive

dysinesia. To date, risperidone has not /een associated ith congenita' "a'# for"ations in

h!"ans $DA pregnancy category =%.

:isperidone has so"e dr!g#dr!g interactions /eca!se certain eny"e ind!cers s!ch ascar/a"aepine can decrease ser!" risperidone concentrations.

7n s!""ary, risperidone is efective for ac!te "ania, /oth as "onotherapy and as ad6!nctive

therapy, /!t 'acs a 'onger#ter" /ipo'ar treat"ent indication. Sedation, eight gain, and

"eta/o'ic pro/'e"s "ay 'i"it the !ti'ity of this agent, partic!'ar'y in 'onger#ter" treat"ent.

?!etiapine. ?!etiapine received DA approva' for the treat"ent of schio# phrenia in ())* and

for the treat"ent of ac!te "anic episodes associated ith /ipo'ar disorder, either as "onotherapy

or as ad6!nctive therapy to 'ithi!" or diva'proe, in 2++4. Patients ith rapid cyding and "ied

episodes ere not in# c'!ded in the origina' ac!te "ania st!dies. :ecent contro''ed evidences!ggests efficacy as "onotherapy for ac!te "anic episodes associated ith /ipo'ar dis#

order in chi'dren and ado'escents ages (+#(* years $De'3e''o et a'. 2++*%, /!t this !se has not yet

/een approved /y the DA. This iss!e is disc!ssed in =hapter (+ of this vo'!"e. 7n 2++0,

5!etiapine as approved for the treat"ent of /ipo'ar depression $=a'a/rese et a'. 2++8C Thase et

a'. 2++0%, as descri/ed in =hapter * of this vo'!"e. 7n addition, in 2++1, 5!etiapine added to

'ithi!" or va'proate as approved for the 'onger#ter" treat"ent of /ipo'ar 7 disorder $S!ppes et

a'. 2++)C Lieta et a'. 2++1/%, as descri/ed in =hapter 1 of this vo'!"e. An etended#re'ease

for"!'ation of 5!etiapine $5!etiapine E:% as approved for the treat"ent of schiophrenia in

2++* and in 'ate 2++1 received indications for "onotherapy or ad6!nctive therapy of ac!te "anic

or "ied episodes, "onotherapy treat"ent of /ipo'ar depression, and ad6!nctive /ipo'ar "aintenance treat"ent.

M!'ticenter, do!/'e#/'ind, p'ace/o#contro''ed tria's esta/'ished the efficacy of 5!etiapine

"onotherapy in ac!te "ania and 5!etiapine E: "onotherapy in ac!te "anic or "ied episodes

$3oden et a'. 2++8C Mc'ntyre et a'. 2++8%.

7n addition, "!'ticenter, rando"ied, do!/'e#/'ind, p'ace/o#contro''ed st!dies confir"ed the

efficacy of ad6!nctive $added to 'ithi!" or diva'proe% 5!etiapine in ac!te "ania $Sachs et a'.

2++4C atha" et a'. 2++4%.

7n contro''ed c'inica' st!dies, the 5!etiapine dosage "ost often as (++ "g on day (,2++ "g on

day 2, -++ "g on day -,4++ "g on day 4, !p to 0++ "g on day 8, and !p to 1++ "g thereafter,

and the "ean fina' 5!etiapine dosages in re# sponders ere approi"ate'y 4-+#8++ "gNday for

"onotherapy and approi# "ate'y 4-+#8*8 "gNday for ad6!nctive therapy. This approach is th!s

the reco""ended regi"en in the U.S. prescri/ing infor"ation. ?!etiapine E: as

started at -++ "g at /edti"e, increased to 0++ "g at /edti"e on day 2, and s!/# se5!ent'y dosed

/eteen 4++ and 1++ "g at /edti"e.

The "ost co""on adverse events ith 5!etiapine are so"no'ence, diiness $post!ra'

hypotension%, dry "o!th, constipation, increased a'anine trans# a"inase, eight gain, and

dyspepsia.

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"onotherapy yie'ded "ore so"no'ence, etrapyra"ida' sy"pto"s diiness, agitation, and

discontin!ations /eca!se of adverse events.

@iprasidone is avai'a/'e in a rapid#acting intra"!sc!'ar for"!'ation that is indicated for the

treat"ent of ac!te agitation in schiophrenic patients for ho" treat"ent ith iprasidone is

appropriate and ho need intra"!sc!'ar anti# psychotic "edication for rapid contro' of agitation, /!t intra"!sc!'ar iprasi

done has not /een approved for the treat"ent of /ipo'ar disorder. >oever, intra"!sc!'ar

iprasidone appeared to yie'd /enefit at (+#2+ "g $!p to fo!r doses in 24 ho!rs% in psychotic

agitated patients ith /ipo'ar disorder $"anic or "ied episodes ith psychotic feat!res% or

schioaffective disorder, /ipo'ar type, in a s!/gro!p ana'ysis of to si"i'ar'y designed s"a'', 24#

ho!r, rando"ied, do!/'e#/'ind, fied#dose st!dies $Danie' et a'. 2++4%.

7n ac!te "ania st!dies, ora' iprasidone as started at 4+ "g tice per day ith food, increased

to 0+ or 1+ "g tice per day ith food on the second day, and s!/se5!ent'y ad6!sted as neededand to'erated ithin the range of 4+#1+ "g tice per day ith food. 7ntra"!sc!'ar iprasidone

has a reco""ended dosage for agitation in schiophrenia of (+ "g every 2 ho!rs $or 2+ "g

every 4 ho!rs% as needed !p to 4+ "gNday. 7n c'inica' practice, 'oer $e.g., X1+ "gNday%

co"pared ith higher $e.g., at 'east 1+ "gNday% ora' iprasidone dosages "ay increase the ris of

aathisia $Ora' et a'. 2++0%, so that opti"a' titration of this

agent "ay invo've avoiding 'oer dosages to prevent aathisia or a/r!pt'y increasing to higher

dosages if aathisia deve'ops at 'oer dosages. Ad6!nctive 'oraepa" !sed in c'inica' tria's "ay

have decreased pro/'e"s ith aathisia.

The "ost co""on adverse events associated ith discontin!ation of iprasi#done in ac!te "aniaere aathisia, aniety, depression, diiness, dystonia, rash, and vo"iting. The "ost co""on

adverse events ith intra"!sc!'ar iprasidone in schiophrenic patients ere headache, na!sea,

and so"no'ence.

The U.S. prescri/ing infor"ation for iprasidone inc'!des a /oed arning regarding the

increased ris of "orta'ity $pri"ari'y cardiovasc!'ar or infectio!s% in e'der'y patients ith

de"entia#re'ated psychosis $an antipsychotic c'ass arning%. The DA has stip!'ated that the

iprasidone U.S. prescri/ing in# for"ation inc'!de the riss of hyperg'yce"ia and dia/etes

"e''it!s, /!t the report of a recent consens!s deve'op"ent conference s!ggested that the riss of

o/esity, dia/etes, and hyper'ipide"ia ith this agent ere si"i'ar to those ith aripiprao'e andere 'ess than ith other second#generation antipsychotics $PhysiciansV Des :eferettce 2++1%.

Th!s, c'inica' and $as indicated% 'a/oratory "onitoring for o/esity, dia/etes, and hyper'ipide"ia

"ay /e pr!dent for patients receiving iprasidone. Other arnings in the prescri/ing infor"ation

inc'!de the riss of ne!ro'eptic "a'ignant syndro"e, tardive dysinesia, ?T pro'ongation, and

s!dden death. 7n a recent epide"io'ogica' st!dy, c!rrent !se of first# and second#generation

antipsychotics as associated ith dose#re'ated increases in rates of s!dden cardiac death $(.))

and 2.20, respective'y% $:ay et a'. 2++)%. A'tho!gh pre"areting st!dies s!ggested that

iprasidone yie'ded cardiac cond!ction de'ays, post"areting eperience to date has fai'ed to

indicate c'inicaUy significant pro/'e"s ith cardiac cond!ction. To date, iprasi# done has not

/een associated ith congenita' "a'for"ations in h!"ans $DA pregnaney category =%.

@iprasidone has so"e dr!g#dr!g interactions /eca!se certain eny"e in# d!cers s!ch as

car/a"aepine can decrease ser!" iprasidone concentrations, and so"e eny"e inhi/itors s!ch

as "acro'ide anti/iotics "ay increase ser!" iprasidone concentrations. The dinicai significance

of these interactions re"ains to /e deter"ined. 7n addition, co"/ining iprasidone ith

antiarrhyth"ic "edications is not reco""ended /eca!se of concerns a/o!t the potentia'

for additive cardiac cond!ction de'ays.

7n s!""ary, iprasidone is effective for ac!te "ania /!t 'acs a 'onger#ter" /ipo'ar treat"ent

indication. Sedation, eight gain, and "eta/o'ic conce"s appear to /e "!ch 'ess pro/'e"atic

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ith iprasidone co"pared ith so"e other second#generation antipsychotics, a'tho!gh dosing

co"p'eity and aathisia "ay 'i"it its !ti'ity in so"e patients.

Ar ipiprao'e. Aripiprao'e received DA approva' for the treat"ent of schio#

in 2++2C as "onotherapy for the treat"ent of ac!te "anic or "ied episodes associated ith

/ipo'ar disorder in ad!'ts in 2++4 and in chi'dren and adoiescents ages (+#(* years in 2++1C asad6!nctive therapy $added to 7tthi!" or va'proate% in ad!'ts, chi'dren, and adoiescents in 2++1C

and as 'onger#ter" "onotherapy treat"ent for /ipo'ar 7 disorder in ad!'ts in 2++8 and in chi'dren

and adoiescents in 2++1. The !se of aripiprao'e for ac!te "anic and "ied episodes in chi'dren

and adoiescents is descri/ed in =hapter (+ of this vo'!"e. Aripiprao'e as approved as an

ad6!nctive treat"ent to antidepressants for "a6or depressive disorder in 2++*. Arapid#acting

intra"!sc!'ar for"!'ation of aripiprao'e as indicated for the treat"ent of agitation associated

ith schiophrenia or /ipo'ar disorder, "anic or "ied episodes, in 2++0.

M!'ticenter, do!/'e#/'ind, p'ace/o#contro''ed tria's esta/'ished the effi# cacy of aripiprao'e

"onotherapy in ac!te "ania $Kec et a'. 2++-aC Sachs et a'. 2++0%. 7n a poo'ed ana'ysis of ac!te"ania st!dies, aripiprao'e "onotherapy appeared to have a /road spectr!" of efficacy $S!ppes

et a'. 2++1%. Th!s, aripiprao'e had co"para/'e /enefits in patients ith "ore severe $/ase'ine

o!ng Mania :ating Sca'e HM:SJ score21% or 'ess severe $/ase'ine M:S score X

21% "ania, ith "anic or "ied episodes, ith or itho!t psychotic sy"pto"s, and ith or

itho!t rapid cyc'ing.

7n addition, a "!'ticenter, do!/'e#/'ind, p'ace/o#contro''ed tria' assessed aripiprao'e co"pared

ith ha'operido' "onotherapy in ac!te "ania $Lieta et a'. 2++8%. 9fficacy as co"para/'e, /!t

aripiprao'e co"pared ith ha'operido' yie'ded feer etrapyra"ida' sy"pto"s and 'ess

aathisia. Other adverse events o/served ith /oth agents inc'!ded tre"or, headache, depression,and inso"nia.

To "!'ticenter, do!/'e#/'ind, p'ace/o# and active co"parator#contro''ed tria's indicated

aripiprao'e "onotherapy co"pared ith 'ithi!" "onotherapy $Kec et a'. 2++*% and

ha'operido' "onotherapy $Sanche et a'. 2++1% in ac!te "ania yie'ded co"para/'e efficacy and

to'era/i'ity, a'tho!gh ha'operido' yie'ded "ore etrapyra"ida' sy"pto"s.

A "!'ticenter, do!/'e#/'ind, p'ace/o#contro''ed tria' indicated that ad6!nctive aripiprao'e $added

to 'ithi!" or va'proate% as effective in ac!te "ania $Lieta et a'. 2++1a%.

A "!'ticenter, do!/'e#/'ind, p'ace/o#contro''ed st!dy reported the efficacy of a rapid#acting

intra"!sc!'ar for"!'ation of aripiprao'e for the treat"ent of agitation associated ith "anic or

"ied episodes $@i"/roff et a'. 2++*%.

7n ear'y ad!'t ac!te "ania st!dies, ora' aripiprao'e as started at -+ "gNday and co!'d /e

red!ced to (8 "gNday for to'era/i'ity if needed, ith "ean fina' dai'y dosages /eing

approi"ate'y 21 "gNday. >oever, in 'ater ad!'t ac!te "ania st!dies, ora' aripiprao'e as

started at (8 "gNday and co!'d /e increased to -+ "gNday for efficacy if needed. The U.S.

prescri/ing infor"ation for the treat"ent of ac!te "anic and "ied episodes in ad!'ts s!ggests

starting ora' aripiprao'e at (8 "gNday, hich as a'so the reco""ended dosage, /!t if

necessary and to'erated, the dosage co!'d /e increased to as high as the "ai"!" dosage of

-+ "gNday. 3eca!se of concerns a/o!t adverse effects, and the 'ac of additiona' /enefit ith

doses higher than ).*8 "g per in6ection in c'inica' tria's, the U.S. prescri/ing infor"ation

reco""ends ad"inistering intra"!sc!'ar aripiprao'e at a dose of ).*8 "g $rather than (8 "g%

per in6ection, or 8.28 "g intra"!s# c!'ar'y if c'inica''y indicated, and repeating ).*8#"g $or

8.28#"g% intra"!sc!'ar in6ections as often as every 2 ho!rs as necessary and to'erated, ith a

"ai"!" of-+ "gNday.

Perhaps /eca!se of partia' agonist effects at dopa"ine receptors, na!sea and vo"iting can occ!r

hen aripiprao'e is started. To'era/i'ity "ay /e en# hanced in patients ith gastrointestina' or

other adverse effects if aripiprao'e is initiated at (8 "g or 'oer in divided doses for a fe days

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/efore /eing increased to as "!ch as -+ "gNday. Ad6!nctive 'oraepa" !sed in c'inica' tria's "ay

have decreased pro/'e"s ith aathisia. So"no'ence and constipation "ay /e en#

co!ntered ith aripiprao'e, /!t eight gain is 'ess of a concern than ith o'an# apine,

5!etiapine, and risperidone.

The U.S. prescri/ing infor"ation for aripiprao'e inc'!des /oed arnings regarding theincreased riss of (% "orta'ity $pri"ari'y cardiovasc!'ar or infectio!s% in e'der'y patients ith

de"entia#re'ated psychosis $an antipsychotic dass arning% and 2% s!idda'ity $rdated to !se of

antidepressant dr!gs in patients !p to age 24 years and /ased on an antidepressant dass arning%.

The DA has stip!'ated that the aripiprao'e U.S. prescri/ing infor"ation inc'ode

the riss of hyperg'yce"ia and dia/etes "e''it!s, /!t the report of a recent consens!s

deve'op"ent conference s!ggested that the riss of o/esity, dia/etes, and hyper'ipide"ia ith

this agent ere si"i'ar to those ith iprasidone and 'ess than ith other second#generation

antipsychotics $PhysiciansV Des :eference 2++1%. Th!s, dinica' and $as indicated% 'a/oratory

"onitoring for o/esity, dia/etes, and hyper'ipide"ia "ay /epr!dent for patients receiving

aripiprao'e. Other arnings in the prescri/ing infor"ation inc'!de the riss of cere/rovas# c!'ar

adverse events, indnding stroe, in e'der'y patients ith de"entiaC ne!ro# 'eptic "a'ignant

syndro"eC and tardive dysinesia. To date, aripiprao'e has not /een assodated ith congenita'

"a'for"ations in h!"ans $DA pregnancy category=%.

Aripiprao'e has so"e dr!g#dr!g interactions /eca!se eny"e ind!cers s!ch as car/a"aepine

can decrease ser!" aripiprao'e concentrations and so"e eny"e inhi/itors s!ch as "acro'ide

anti/iotics "ay increase ser!" aripiprao'e concentrations.

7n s!""ary, aripiprao'e is effective for ac!te "ania and has a 'onger#ter" /ipo'ar treat"ent

indication, so patients ith ac!te anti"anic responses a'so "ay /e good candidates for 'onger#ter" aripiprao'e therapy. A'tho!gh seda# tion, eight gain, and "eta/o'ic concerns "ay /e 'ess

pro/'e"atic ith aripiprao'e than ith so"e other second#generation antipsychotics, aathisia

"ay 'i"it its !ti'ity in so"e patients.

Tier //: 4ig(-riorit 5napproved Acute Mania

Treatment #ptions

As noted ear'ier, safety and to'era/i'ity 'i"itations $partic!'ar'y in the 'onger ter"%Y of so"e Tier

7 approved "edications for the treat"ent of ac!te "ania "ay 'ead c'inicians and patients to

consider other options. When assessing a'te"ative treat"ents, one approach is to consider potentia''y approva/'e "edications, s!ch as ne second#generation antipsychotics. One s!ch

agent&asenapine&has not yet /een approved /y the DA for the treat"ent of ac!te "ania or

schiophrenia, or "areted in the United States, /eca!se the pivota' tria's descri/ed in this

section are sti'' !nder revie. 7t is anticipated that in the near f!t!re, asenapine and possi/'y

other ne second#generation antipsychotics i'' /e approved.

To positive "!'ticenter, rando"ied, do!/'e#/'ind, p'ace/o#contro''edtria's s!ggested that

asenapine "ay !'ti"ate'y /e approved for the treat"ent of ac!te "anic and "ied episodes in

patients ith /ipo'ar 7 disorder $Mc'ntyre et a'. 2++1%.

7n a poo'ed ana'ysis of the to pivota' st!dies, asenapine and o'anapine ere /oth s!perior to

p'ace/o, yie'ding Ts of 1 and 8, respective'y $ig!re 0#-, 'eft side%, /!t /oth a'so ca!sed

eight gain, yie'ding >s of (* and *, respective'y $ig!re 0#-, right side%. >ead#to#head

co"parisons indicated that o'anapine co"pared ith asenapine as "ore effacio!s $TB ((C

PX+.+(% /!t yie'ded "ore eight gain $>#''C PcO.OO'%. Th!s, for o'anapine co"pared ith

asenapine, the efficacy advantage as offset /y a co"para/'e to'era/i'ity disadvantage. Th!s, for

o'anapine co"pared ith asenapine, for every additiona' responder, one co!'d epect an

additiona' patient ith dinica''y significant $ *F increase% eight gain.

3a'ancing /enefits and riss is a cr!cia' co"ponent of treat"ent se'ection. or so"e patients

ith very ac!te and very severe "ania ho 'ac s!/stantive eight or "eta/o'ic pro/'e"s, the

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efficacy advantage of o'anapine "ay "ae it "ore attractive. 7n contrast, for other patients ith

'ess ac!te and 'ess severe "ania ho have s!/stantive eight or "eta/o'ic pro/'e"s, the

to'era/i'ity advantage of asenapine "ay "ae it "ore attractive.

Tier ///: intermediate-riorit #t(er Acute Mania

Treatment #ptions

The "anage"ent of ac!te "ania is s!fficient'y cha''enging that dinica' need "ay o!tstrip the

previo!s'y disc!ssed evidence#/ased treat"ent options. 7n this section, e consider other $in

"ost instances !napproved% treat"ent options ith to'era/i'ity 'i"itations andNor "ore 'i"ited

evidence of efficacy co"pared ith the Tier 7 and 77 treat"ents. These a'ternatives inc'!de other

"ood sta/i'iers $car/a"aepine%, first#generation antipsychotics $ch'orpro"aine, thioridaine,

thioth/cene, pi"oide, and ha'operido'%, other second# generation antipsychotics $doapine%,

ad6!nctive /enodiaepines, and 9=T. 7n genera', treat"ent g!ide'ines do not consider these

"oda'ities to /e first#'ine interventions /!t dte the" as inter"ediate#priority options $A"erican

Psychiatric Association 2++2C Ioodin 2++-C Ir!ne et a; 2++2C Kec et a'. 2++4C S!ppes et a'.

2++8C atha" et a'. 2++0%. >oever, so"e Tier 777 options have "itigating advantages that "ight

"ae the" attractive for se'ected patients,

"igure 6-. T(ree-%ee! double-blind asenapine monot(erap versus olanapine

monot(erap versus placebo in acute mania.

!"/er needed to treat $T%, n!"/er needed to hartn $>%, and response and c'inica''y

significant $*F increase% eight gain rates are shon. Asenapine "onotherapy $/'ac /ars% and

o'anapine "onotherapy $gray /ars% co"pared ith p'ace/o "onotherapy $hite /ars% had

s!perior efficacy /!t yie'ded "ore c'inica''y significant eight gain. or o'anapine co"pared

ith asenapine, the efficacy advantage as offset /y a co"para/'e to'era/i'ity disadvantage.

M:SBo!ng Mania :ating Sca'e. PX+.+(, PX+.++(, +.+++( vers!s p'ace/o.

Source. Adapted fro" Mc'ntyre et a'. 2++1.

and in certain circ!"stances, so"e of these interventions "ay /e considered ear'y on $e.g., 9=T

in pregnant o"en%.

#t(er Mood 0tabiliers: 7arbamaepine

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Despite car/a"aepineVs having approva' for the treat"ent of ac!te "ania, co"p'eity of !se

re'ated to dr!g interaction as e'' as to'era/i'ity 'i"itations and 'ess co"pe''ing evidence of

"aintenance efficacy 'ed to this "edication /eing considered as an a'te"ative rather than a first#

'ine anti"anic agent. everthe'ess, se'ected patients ho report inade5!ate efficacy andNor

to'era/i'ity ith Tier 7 or 77 options "ay find car/a"aepine a orthhi'e a'te"ative.

The anticonv!'sant car/a"aepine has /een avai'a/'e for the treat"ent of epi'epsy in the United

States since ()*4. 7n the ()1+s, contro''ed car/a"aepine st!dies !sing active co"parator and

on#off#on designs provided pre'i"inary evidence of efficacy in ac!te "ania. 3eca!se of

econo"ic conce"s s!ch as patent protecdon 'i"itations and the high cost of o/taining DA

approva', a car/a"aepine indication in ac!te "ania as not initia''y so!ght in the United States

/!t as o/tained fro" agencies in =anada, apan, A!stra'ia, and severa' 9!ropean

co!ntries. As noted a/ove, the a/sence of an DA indication and co"p'eity of !se 'ed

car/a"aepine to /e considered an a'te"ative rather than a first#'ine intervention in ac!te "ania

$A"erican Psychiatric Association 2++2%. >oever, event!a''y "!'ticenter, rando"ied, do!/'e#

/'ind, p'ace/o#contro''ed tria's confir"ed the efficacy of a proprietary /eaded, etended#re'ease

caps!'e for" U#'ation of car/a"aepine in ac!te "anic and "ied episodes $Weis'er et a'.

2++4a, 2++8%, yie'ding an DA indication for this for"!'ation in 'ate 2++4.

O'der st!dies s!ggested !ti'ity for car/a"aepine co"/ined ith 'ithi!" $Kra"'inger and Post

()1)% or antipsydiotics $O!"a et a'. ()1)% in the treat"ent of ac!te "ania. >oever,

car/a"aepine can increase the hepatic "eta/o'is" of "!'tip'e other agents, potentia''y

co"pro"ising the efficacy of co"/ination therapies $Ketter et a'. ())(a, ())(/%. 7n a s!/se5!ent

st!dy that ree"phasied this point, car/a"aepine yie'ded s!/stantia' decreases in /'ood

risperidone concentrations, co"pro"ising efficacy of the co"/ination in the treat"ent of

ac!te "ania $atha" et a'. 2++-%. 7n another co"/ination therapy st!dy, car# /a"aepine yie'ded

'oer than epected /'ood o'anapine concentrations, and even tho!gh this as addressed in part

/y "ore aggressive o'anapine dosing, the efficacy of the o'anapine p'!s car/a"aepine

co"/ination as sti'' not significant'y /etter than that of car/a"aepine "onotherapy in the

treat"ent of ac!te "ania $Tohen et a'. 2++1%. >oever, o'anapine p'!s car/a"aepine

co"pared ith car/a"aepine "onotherapy yie'ded higher trig'yceride 'eve's and "ore fre5!ent

c'inica''y significant $S *F% eight ga'n.

To 'i"it ear'y adverse effects, car/a"aepine is co""on'y introd!ced at 'o $(++#4++ "gNday%

dosages and grad!a''y increased, !nti' therape!tic efficacy is ade5!ate, adverse effectss!pervene, or ser!" concentrations eceed (2 ZEgN";. 9!thy"ic or depressed co"pared ith

"anic patients tend to /e 'ess a/'e to to'erate adverse effects and th!s "ay re5!ire "ore grad!a'

initiation. A' tho!gh response in /ipo'ar disorder does not appear re'ated to ser!" concen#

trations, the 4#(2 pgN"; range fro" epi'epsy "ay /e considered as a /road target, and ser!"

car/a"aepine concentrations "ay /e !sed as phar"acoinetic checs for etre"e va'!es.

=ar/a"aepine has severa' i"portant 'i"itations and has /oed arnings in the U.S. prescri/ing

infor"ation regarding the riss of serio!s der"ato'ogica' reactions and the > ;A#3(8+2 a''e'e,

as e'' as ap'astic ane"ia and agran!'ocytosis. =ar/a"aepine isa'so associated ith co""on

/enign 'e!openia, hich in rare instances "ay /e an ear'y indication of serio!s /'ood dyscrasia.Other arnings in the prescri/ing infor"ation inc'!de the riss of teratogenicity and increased

intraoc!'ar press!re as a res!'t of "i'd anticho'inergic activity.

7n 2++1, theDA re'eased an a'ert regarding increased ris of s!icida'ity $s!icida' /ehavior or

ideation% in patients ith epi'epsy as e'' as psychiatric disorders for (( anticonv!'sants

$ind!ding car/a"aepine%. The re'ative ris for s!icida'ity as higher in the patients ith

epi'epsy co"pared ith those ith psychiatric disorders.

As disc!ssed in =hapter (( of this vo'!"e, car/a"aepine has the potentia' for teratogenicity

$DA pregnancy category D%, ind!ding craniofacia' defects, fingernai' hypop'asia, and

deve'op"enta' de'ay in approi"ate'y ((F&20F and spina /ifida in approi"atdy -F.

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=ar/a"aepine is a'so associated ith co""on /enign rashes, hich in rare instances "ay /e

har/ingers of rare serio!s rashes. >oever, in occasiona' patients, car/a"aepine "ay /e /etter

to'erated than other agents, and data contin!e to s!pport the notion that one potentia' advantage

of car/a"aepine is the re'ative'y 'o ris of c'inica''y sig# nificant eight gain $Ketter et a',

2++4%,

=ar/a"aepine dr!g interactions can yie'd car/a"aepine toicity $e.g., hen erythro"ycin or

va'proate is added to car/a"aepine% and inefficacy of other "edications $e.g., hor"ona'

contraceptives and "!'tip'e psychotropic dr!gs, ind!ding severa' neer anticonv!'sants and

seeond#generation antipsy# chotics%. Additiona' infor"ation a/o!t car/a"aepine is provided in

=hapter (-.

7n s!""ary, car/a"aepine is an option for ac!te "ania that has dr!g in# teraction and

to'era/i'ity 'i"itations. 7n addition, in contrast to 'ithi!" and di# va'proe, evidence s!pporting

the !se of car/a"aepine in the 'onger#ter" "anage"ent of /ipo'ar disorders is 'i"ited. Th!s,

car/a"aepine is considered an inter"ediate#priority ac!te "ania therapy /y "!'tip'e treat"entg!ide'ines. everthe'ess, se'ected patients, partic!'ar'y those ho are not taing "!'tip'e

"edications and report inade5!ate efficacy andNor to'era/i'ity ith Tier 7 or 77 options, "ay find

car/a"aepine a !sef!' treat"ent for ac!te "ania.

"irst-2eneration Antipsc(otics

irst#generation antipsychotics, a'so referred to as typica' antipsychotics, fig!re i"portant'y in

the history of treat"ent of /ipo'ar disorders /!t in recent years have /een s!perseded /y second#

generation antipsychotics, pri"ari'y /eca!se the 'atter have "ore favora/'e adverse#effect

profi'es. M!'tip'e first#generation antipsychotics ere approved /y the DA for the treat"ent of schiophrenia in the ()8+s, ()0+s, and ()*+s, /!t on'y one s!ch agent, ch'orpro"aine, as

event!a''y approved for ac!te "ania.

7ndivid!a' ear'y st!dies fo!nd that first#generation antipsychotics co"pared ith 'ithi!" tended

to have co"para/'e overa'' efficacy, ith advantages ear'y in treat"ent for rapid contro' of

agitation in high'y active patients /!t disadvan# tages 'ater in treat"ent co"pared ith 'ithi!"

for achieving re"ission of the f!'' "anic syndro"e s!fficient to per"it discharge $Iarfine' et

a'. ()1+C ohnson et a'. ()01,()*(C Prien et a'. ()*2C Shopsin et a'. ()*8%. >oever, a "eta#

ana'ysis of five contro''ed ac!te "ania tria's $ohnson et a'. ()01,()*(C Shopsin et a'. ()*8C

Spring et a'. ()*+C Taahashi et a'. ()*8% fo!nd the poo'ed response rate ith 'ithi!" $1)F%s!perior to that ith ne!ro'eptics $-1F% $anica et a'. ())2%. 7n so"e st!dies, co"/ining first#

generation antipsychotics ith 'ithi!" appeared to yie'd enhanced therape!tic effects $Iarfine'

et a'. ()1+C S"a'' et a'. ())8%.

7n the ()*+s and ()1+s, A"erican psychiatrists, perhaps "ore foc!sed on the 'ater advantages of

'ithi!", tended to consider first#generation antipsychotics as ad6!ncts for ac!te "ania, ith

'ithi!" /eing the pri"ary treat"ent for /oth ac!te "ania and "aintenance. 7n contrast, 9!ropean

psychiatrists, perhaps "ore foc!sed on the ear'ier advantages of first#generation antipsychotics,

tended to consider first#generation antipsychotics to /e the pri"ary treat"ents for ac!te "ania

and 'ithi!" as an ad6!nct in ac!te "ania /!t the pri"ary /ipo'ar "aintenance treat"ent. >ence

first#generation antipsychotics ere nottho!ght to /e fo!ndationa' treat"ents for /ipo'ar

disorders /!t ere considered to /e pri"ari'y for ac!te "ania, ith !ni"oda' activity atten!ating

"anic

sy"pto"s, so"eti"es at the cost of eacer/ating depressive sy"pto"s. or ea"p'e, these

agents ere i"p'icated in yie'ding post"ania depression in so"e $K!op!'os et a'. ()1+C

Morgan ()*2%, /ot not a'' $;!cas et a'. ()1)%, st!dies.

everthe'ess, first#generation antipsychotics ere co""on'y !sed $often in co"/ination ith

'ithi!"% for the treat"ent of ac!te "ania on /oth sides of the At'antic in the ()*+s and ()1+s,

/!t this changed as the to'era/i'ity 'i"itations of first#generation antipsychotics /eca"e "ore

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evident and ne treat#"ent options e"erged. Th!s, the ro'e of first#generation antipsychotics in

the "anage"ent of /ipo'ar disorders /eca"e increasing'y 'i"ited /eca!se of concerns a/o!t

ac!te etrapyra"ida' sy"pto"s $asra''ah et a'. ()11%, tardive dysinesia $Kane and S"ith

()12%, and ind!ction of dysphoria $Ah'fors et a'. ()1(%, pro/'e"s that ere "!ch 'ess of a

conce" ith second#generation anti# psychotics.

The rapid onset of action of first#generation antipsychotics as partic!'ar'y evident ith

intra"!sc!'ar ad"inistration. 7ndeed, intra"!sc!'ar ha'operido' $often co"/ined ith 'oraepa"

to enhance efficacy and diphenhydra"ine to decrease etrapyra"ida' sy"pto"s% persisted as an

i"portant treat"ent for ac!te agitation even into the era of second#generation antipsychotics,

a'tho!gh this as event!a''y cha''enged /y the avai'a/i'ity of intra"!sc!'ar f/r"!'ations

of agents s!ch as o'anapine, iprasidone, and aripiprao'e.

The !se of first#generation antipsychotics in ac!te "ania, partic!'ar'y ha'operido' $in vie of the

'arge a"o!nt of data s!pporting its !se%, is descri/ed in the fo''oing s!/sections. Additiona'

infor"ation a/o!t first#generation anti# psychotics is provided in =hapter (-.

7(lorpromaine. =h'orpro"aine, the prototypica' first#generation anti# psychotic, as non

to re'ieve ac!te agitation as ear'y as ()82 $De'ay et a'. ()82C ;eh"ann and >anrahan ()84% and

as approved /y the DA for the treat"ent of schiophrenia in ()84 and to contro' the

"anifestations of the "anic type of "anic#depressive i''ness in ()*-. =ontro''ed tria's

esta/'ished the efficacy of ch'orpro"aine in ac!te "ania as "onotherapy $Posi et a' ()1+C Prien

et a'. ()*2C Shopsin et a'. ()*8% and in co"/ination ith 'ithi!" $=ooson et a'. ()1(C anica et

a' ()11%. >oever, the dinica' !ti'ityof this 'o#potency first generation antipsychotic as

'i"ited /y pro"inent sedation and hypotension, hich res!'ted in increased !se of inter"ediate#

and high#potency agents, partic!'ar'y ha'operido'.

T(ioridaine' t(iot(ixene' and pimoide. =ontro''ed tria's a'so reported efficacy in ac!te "ania

for the 'o#potency agent thioridaine $Post et a'. ()1+% and

the high#potency agents thiothiene $anicaeta'. ()11% and pi"oide $=ooson et a'. ()1(C Post

et a'. ()1+%.

>a'operido'. The high#potency first#generation antipsychotic ha'operido', co"pared ith the

'o#potency agent ch'orpro"aine, yie'ds s!/stantia''y 'esssedation and hypotensidn /!t "ore

fre5!ent etrapyra"ida' adverse effects. 9ar'y tria's s!ggested that ha'operido' as effective in

ac!te "ania /oth as "ono#therapy $Iarfine' et a'. ()1+C Shopsin eta'. ()*8% and as an ad6!nct

to 'ithi!" $Iarfine' et a'. ()1+%.

7n ac!te agitation in schiophrenia or "aniai, intra"!sc!'ar ha'operido', 8 "g, co"pared ith

intra"!sc!'ar 'oraepa", 2 "g, in6ections every -+#0+ "in!tes as needed appeared to have

si"i'ar efficacy, a'tho!gh ha'operido' yie'ded "ore etrapyra"ida'adverse effects $3ienie et a'.

())1C oster et a'. ())*%. >oever, co"/iningthese agents appeared toyie'd "ore rapid/enefit

co"pared ith either as "onotherapy and perhaps even feer etrapyra"ida' sy"pto"s

co"pared ith ha'operido' "onotherapy $3attag'ia eta'. ())*%.

Sevefa' conte"porary "!'ticenter, rando"ied, do!/'e#/'ind, ac!te "ania st!dies of second#generation antipsychotics have inc'!ded ha'operido' as an active co"parator, providing a

s!/stantia' a"o!nt of data s!pporting its efficacy in the treat"ent of ac!te "ania as "onotherapy

$Mc'ntyre et a'. 2++8C S"!'evich et a'. 2++8C Tohen et a'. 2++-C Lieta et a'. 2++8% and as an

ad6!nct to 'ithi!" or va'proate $Sachs et a'. 2++2%.

=onte"porary ac!te "ania st!dies co"pared ith ear'y st!dies have !sed "ore consistent and

conservative ha'operido' dosages, ith "ean dosages ranging /eteen 8 and (( "gNday

$"ini"!" 2#(+ "gNdayC "ai"!" (+#(8 "gNday% for "onotherapy $S"!'evich et a'. 2++8C

Tohen et a'. 2++-C Lieta et a'. 2++8% and the "ean dosage heing 0.2 "gNday $"ini"!" dosageB2

"gNdayC "ari"!" dosageB (2 "gNday% for co"/ination therapy $Sachs et a'. 2++2%.

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The U.S. prescri/ing infor"at" for ha'operido' has /een revised to in# c'!de a /oed arning

$'ie other antipsychotics% indicating that it "ay increase "orta'ity in e'der'y patients ith

de"entia#re'ated psyc>osis $Wang et a'. 2++8%. Warnings in the ha'operido' prescri/ing

infor"ation inc'!de the riss of cardiovasc!'ar effects $s!dden death, ?Tc pro'ongation, and

torsades de pointes%, tardive dysinesia, ne!ro'eptic "a'ignant syndro"e, teratogenicity,

/roncho#pne!"onia, and an encepha'opathic syndro"e $eanessC 'ethargyC feverC

tre"!'o!snessC conf!sionC etrapyra"ida' sy"pto"sC 'e!ocytosisC and e'e# vated serinn

eny"es, ser!" !rea nitrogen, and fasting /'ood s!gar% fo''oed /y irreversi/'e /rain da"age

hen co"/ined ith 'ithi!". The 'atter iss!e is

considered in greater detai' /y Ketter and Wang in the section on 'ithi!" in =hapter (- of this

vo'!"e. 7n a recent epide"io'ogica' st!dy, c!rrent !se of first# and second#generation

antipsychotics as assodated ith dose#re'ated increases in rates of s!dden cardiac death $(.))

and 2.20, respective'y% $:ay et a'. 2++)%.

7n s!""ary, so"e first#generation antipsychotics $partic!'ar'y ch'orpro"aine and ha'operido'%have evidence s!pporting their efficacy in ac!te "ania, /!t safetyNto'era/i'ity conce"s

co""on'y res!'t in first#generation antipsychotics /eing he'd in reserve for patients ith

inade5!ate efficacy or to'era/i'ity ith "ood sta/i'iers and second#generation antipsychotics in

Tiers 7 and 77.

#t(er 0econd-2eneration Antipsc(otics: 7loapine

='oapine is the on'y second#generation antipsychotic ith an DA schiophrenia indication

that 'acs an ac!te "ania indication. ;i"ited data s!pport the effectiveness of this agent in

/ipo'ar disorders, /!t safety and to'era/i'ity considerations 'i"it its !ti'ity.

After its introd!ction in dinica' st!dies in the United States in the ear'y ()*+s, c'oapine as

ithdran in ()*4 /eca!se of the ris of agran!'ocytosis and as not approved for c'inica' !se

in the treat"ent of schiophrenia in the United States !nti' ())+. A'tho!gh c'oapine 'acs an

DA indication for ac!te "ania, this "edication as of interest not on'y /eca!se it as the

prototypica' atypica' antipsychotic /!t a'so /eca!se it as the on'y agent approved for treat"ent#

resistant schiophrenia and for decreasing s!icida' /ehavior in patients ith schiophrenia

$Me'ter et a'. 2++-%.

Uncontro''ed reports $for revies, see rye et a'. ())1C @arate et a'. ())8% and to contro''ed

tria's $3ar/ini et a'. ())*C S!ppes d a'. ()))% s!ggested that c'oapine "ight have efficacy in

/ipo'ar disorders. 7n p!/'ished reports, "ean c'oapine dosages in patients ith /ipo'ar disorder

ranged fro" approi"ate'y (28 to 88+ "gNday.

>oever, c'oapine genera''y has a cha''enging adverse#effect profi'e co"pared ith other

treat"ent options. The U.S. prescri/ing infor"ation for c'oapine inc'!des /oed arnings

regarding the riss of 7% agran!'ocytosis, 2% sei!res,-%"yocarditis, 4% other adverse

cardiovasc!'ar and respiratory effects, and 8% increased "orta'ity $pri"ari'y cardiovasc!'ar or

infectio!s% in e'der'y patients ith de"entia#re'ated psyehosis $an antipsychotic dass a"#

ing%. >ence this agent tends to /e he'd in reserve for patients ith treat"ent# resistant /ipo'ar

disorders. 7ncreasing conce"s have /een raised regarding the riss of hyperg'yce"ia

and dia/etes "d'it!s ith c'oapine and second#generation antipsychotics. 7n deed, the DA has

stip!'ated changes in the prescri/ing infor"ation not on'y for c'oapine /!t a'so for o'anapine,

risperidone, 5!etiapine, ipr asidone, and aripiprao'e to ref'ect these riss, s!ggesting a c'ass

effect for s!ch pro/'e"s. 7n contrast, the report of a recent consens!s deve'op"ent conference on

antipsychotics and o/esity, dia/etes, and hyper'ipide"ia e"phasied differences a"ong agents,

ith doapine and o'anapine /eing the "ost, risperidone and 5!etiapine /eing 'ess, and

iprasidone and aripiprao'e /eing the 'east i"p6icated $PhysiciansV Des :eference 2++1%. Th!s,

c'inica' and $as indicated% 'a/oratory "onitoring for o/esity, dia/etes, and hyper'ipide"ia

appears pr!dent for patients receiving c'oapine. Other arnings in the prescri/ing infor"ation

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inc'!de the riss of eosinophi'ia and ne!ro'eptic "a'ignant syndro"e. To date, c'oapine has not

/een associated ith congenita' "a'for"ations in h!"ans $DA pregnancy category 3%.

='oapine has so"e dr!g#dr!g interactions /eca!se certain eny"e ind!cers s!ch as

car/a"aepine can decrease ser!" c'oapine concentrations and so"e eny"e inhi/itors s!ch as

"acro'ide anti/iotics "ay increase ser!" doapine concentrations. 7n addition, co"/iningc'oapine ith /one "arro s!ppressants is not reco""ended /eca!se of concerns a/o!t the

potentia' for increasing the ris of agran!'ocytosis. ina''y, concerns have /een raised re#

garding the riss of ecessive sedation and cardiorespiratory depression ith conco"itant

ad"inistration of c'oapine and /enodiaepines.

7n s!""ary, safety and to'era/i'ity concerns and 'i"ited efficacy data co""on'y res!'t in

c'oapine /eing he'd in reserve for patients ith inade5!ate efficacy andNor to'era/i'ity ith

"ood sta/i'iers and second#generation antipsychotics in Tiers 7 and 77 or first#generation

antipsychotics in Tier 777.

Ad8unctive Benodiaepines

3enodiaepines $"ost co""on'y 'oraepa"% "ay have "odest anti"anic activity, partic!'ar'y

as ad6!ncts to contro' agitation ear'y in treat"ent, and "ay/e !sef!' in the treat"ent of co"or/id

arndety.

The !ti'ity of adding 'oraepa" to 'ithi!" $;eno et a'. ())2% or ha'operido' $3attag'ia et a'.

())*% for ac!te agitation has /een confir"ed in contro''ed tria's. 7n a s"a'' $24#patient% 2#ee

do!/'e#/'ind ac!te "ania st!dy, 'oraepa" and donaepa""onotherapy yie'ded response rates

of 0(F and (1F, respective'y $3rade6n et a'. ())+%.

The "odest degree of anti"anic /enefit ith /enodiaepines is doc!"ented /y eperience

derived fro" their co""on !se as ad6!nctive "edications ear'y in the rando"ied phase of

contro''ed tria's of other agents in ac!te "ania. Typica''y, in s!ch tria's, an agent s!ch as

'oraepa" is per"itted as neededfor inso"nia, a"dety, or agitation, starting at approi"ate'y 4

&0 "gNday and tapering to ero over approi"ate'y ( ee. A'tho!gh this intervention "ay

/rief'y atten!ate so"e sy"pto"s in patients i th ac!te "ania, it does not appear to at#

ten!ate the f!'' "anic syndro"e or syste"atica''y interfere ith the a/i'ity toseparate approved

treat"ents fro" p'ace/o, consistent ith ad6!nctive /enodiaepines having at "ost "odest

anti"anic effects. Th!s, in conte"porary ac!te "ania tria's, the contro' intervention of as#needed

'oraepa", psychiatric hospita'iation, and p'ace/o yie'ds an overa'' response rate of

approi"ate'y -+F, and adding an approved anti"anic agent increases the overa'' response rate

to approi"ate'y 8+F.

The hypnotic $Andersen and ;ing6aerde ()0)% and a"do'ytic $3a''enger et a'. ()11% actions

of /enodiaepines can prove c'inica''y /eneficia' in patients ith /ipo'ar disorders /eca!seinso"nia and a"dety are co""on sy"pto"s. or ea"p'e, !p to 2+F of patients ith /ipo'ar

disorders a'so "ay have panic disorder $MacKinnon et a'. 2++2%. Th!s, Ke ga/apentin and

topira"ate $hich are descri/ed 'ater in this chapter as Tier 7L treat"ents%, /enodiaepines donot appear to /e effecdve as pri"ary treat"ents for /ipo'ar disorders, /!t they "ay yidd

ad6!nctive /enefit in co""on co"or/id pro/'e"s $s!ch as a"dety disorders and inso"nia%.

3enodiaepines are genera''y e''to'erated /!t can ca!se sedation and ataia, especia''y hen

co"/ined ith other agents ith s!ch effects. 3enodiaepines appear to /e associated ith

"inor congenita' "a'for"ations $DA pregnancy category D%. 7n addition, the !d'ity of these

agents is 'i"ited /y their a/!se potentia' $partic!'ar'y in patients ith histories of s!/stancea/!se% and the ris of disinhi/ition $partic!'ar'y in chi'dren and ado'escents and patients

ith ='!ster 3 persona'ity disorders%.

3enodiaepines have so"e noteorthy dr!g interactions. or ea"p'e, concerns have /een

raised regarding the riss of ecessive sedation and cardio# respiratory depression ith

conco"itant ad"inistration of /enodiaepines and c'oapine or intra"!sc!'ar o'anapine.

Additiona' infor"ation a/o!t /en# odiaepines is provided in =hapter (4.

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7n s!""ary, /enodiaepines appear to /e !sef!' ad6!ncts to contro' agitation ear'y in the

treat"ent of ac!te "ania and for the treat"ent of co"or/id a"dety disorders. A'tho!gh /enodiaepines are genera''ye'' to'erated, care is indicated in patient se'ection /eca!se these

agents have a/!se potentia' and "ay yidd disinhi/ition.

Electroconvulsive T(erap

;i"ited contro''ed evidence s!pports a ro'e for 9=T in the treat"ent of ac!te "ania $M!her6ee

et a'. ())4%.

A'tho!gh case reports and case series s!ggested that 9=T "ay /e effective for "ied episodes

$Ir!/er et a'. 2+++C ;iang et a'. ()11C La'enti et a'. 2++1%, a revie /y La'enti and associates

$2++1% indicated that there are varying and fe syste"atic data regarding this iss!e.

Despite the potentia' !ti'ity of 9=T in ac!te "ania, treat"ent#e"ergent affective sitch in ac!te

/ipo'ar depression ith 9=T has /een reported ith varia/'e incidence.

=oncerns /ased on case reports regarding the riss of de'iri!", sei!res, and pro'onged apnea

res!'ted in reco""endations that 'ithi!" not /e co"/ined ith 9=T $S"a'' and Mi'stein ())+%.

7n s!""ary, a'tho!gh so"e evidence s!pports the efficacy of 9=T in ac!te "ania, it is genera''y

he'd in reserve for patients into'erant of or refractory to phar"acotherapy /eca!se of the ris of

cognitive adverse effects, stig"a, consent cha''enges, or 'ogistica' concerns s!ch as coordination

of care and after care. everthe'ess, in certain circ!"stances, 9=T "ay /e considered ear'y on

$e.g., in pregnant o"en ith ac!te "ania%.

Tier /$: *ovel Ad8unctive Treatments

Treat"ent resistance or into'erance and co"or/id conditions are s!fficient'y co""on in patients

ith /ipo'ar disorders that even the a/ove#"entioned ar"a"entari!" "ay /e ins!fficient to

"eet c'inica' needs of so"e patients. 7n this section, e descri/e nove' ad6!nctive treat"ents

ith even "ore 'i"ited evidence of efficacy than the previo!s'y descri/ed treat"ents. These

treat"ents inc'!de other "ood sta/i'iers $'a"otrigine%, other anticonv!'sants $ocar/a#

epine, ga/apentin, topira"ate, tiaga/ine, 'evetiraceta", and onisa"ide%, and ad6!nctive

psychotherapy. Lery caref!' consideration of the specific ro'e$s% of these agents in patients ith

/ipo'ar disorders is arranted. or ea"p'e, for so"e of these interventions, contro''ed tria's

indicate inefficacy in ac!te "ania /!t potentia' efficacy for other phases of /ipo'ar disorder $e.g.,'a"otrigine for 'onger#ter" treat"ent% or in the "anage"ent of co""on co"or/id condi#

tions $e.g., ga/apentin and topira"ate for aniety and a'coho' !se disorders, re# spective'y%. 7n

genera', treat"ent g!ide'ines consider these "oda'ities to /e 'o#priority interventions or not

reco""ended as interventions in the treat"ent of ac!te "ania $A"erican Psychiatric

Association 2++2C Ioodin 2++-C Ir!ne et a'. 2++2C Kec et a'. 2++4C S!ppes et a'. 2++8C

atha" et a'. 2++0%. everthe'ess, so"e Tier 7L options co!'d prove to /e orthhi'e ad6!ncts

for very caref!''y se'ected patients, after consideration ofTier 7&777 treat"ents $e.g., in

patients ith pro"inent co"or/id conditions%.

#t(er Mood 0tabiliers: lamotrigine

The anticonv!'sant 'a"otrigine has a distinctive psychotropic profi'e co"pared ith other "ood

sta/i'iers /eca!se it has a /ipo'ar 'onger#ter" treat"ent indication /!t 'acs an ac!te indication

and appears "ore effective for depressive than for "ood e'evation sy"pto"s. 7n the a/sence of

an ac!te indication, dinicians "ay ponder the opti"a' ti"ing of initiating 'a"otrigine therapy. 7n

"ost instances, this i'' /e d!ring e!thy"ia or syndro"a' or s!/syndro"a' de# pression $on

occasion, i""ediate'y after an ac!te "anic episode% rather than d!ring ac!te "ania.

;a"otrigine as approved for the 'onger#ter" treat"ent of /ipo'ar disorder in 2++-.

;a"otrigine, !n'ie the anticonv!'sants diva'proe and car/a"aepine, does not appear effectivein ac!te "ania $3oden et a'. 2+++C Io'ds"ith et a'. 2++-%.

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7n contrast, do!/'e#/'ind, p'ace/o#contro>ed st!dies fo!nd 'a"otrigine "onotherapy effective in

"aintenance treat"ent $partic!'ar'y for preventing depressive episodes% in /ipo'ar 7 disorder

$3oden et a'. 2++-C =a'a/rese et a; 2++-%. Th!s, as descri/ed in =hapter 1 of this vo'!"e,

'a"otrigine "onotherapy received an DA indication for "aintenance treat"ent in /ipo'ar 7

disorder to day the ti"e to occ!rrence of "ood episodes $depression, "ania, hypo"ania, "ied

episodes% in patients receiving Standard therapy for ac!te "ood ep# isodes. A'so, as descri/ed in

=hapter * of this vo'!"e, contro''ed data s!ggest that 'a"otrigine "ay yie'd "odest /enefits in

ac!te /ipo'ar depression $=a'a#/rese et a'. ())),2++1%, /!t 'a"otrigine does not have an DA

indication for this !se. ina''y, as noted in =hapter ) of this vo'!"e, QManage"ent of :apid#

=yding 3ipo'ar Disorders,R contro''ed data s!ggest that 'a"otrigine "ay /e effective in rapid#

cyding /ipo'ar 77 disorder $a depression#predo"inant s!/type of /ipo'ar 77 disorder% $=a'a/rese et

a'. 2+++% and in treat"ent#resistant $pri"ari'y rapid#cyc'ing /ipo'ar% "ood disorders $rye et a'.

2+++%.

>en

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