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`C S S _ 23_ PR—2ee3 BsDs'E2§§°*:E3*“
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`3287 314356
`uuL 9 «runs a
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`E§<e1_3Es
`Pedigtric Psychopharmacology
`
`
`
`'
`
`-...
`
`Guest Editor-Karen Dineen Wagner, MD
`INTRODUCTION
`
`The Psychopharrnacologic Armanrnentarium
`in the Pediatric Population
`ICD. Wagner
`
`ORIGINAL RESEARCH
`
`Does Comorbid Attention-Deficitrflyperactivity Disorder
`Impact the Clinical Expression of
`Pediatric Obsessive-Compulsive Disorder?
`D./Y. Geller, B. Cgflcy. S. Forearm, at of
`
`RE VIEW
`
`Medication Treatment for Depression
`in Children and Adolescents
`ND. Ryan
`
`nswsw
`Non-Stimulant Treatment of
`Attention-Deficitmyperactivity Disorder
`S.R_ Plisdu
`
`REVIEW
`
`_
`.
`The Use of Mood Stabilizers and_
`Atypical Antipsychotics in Children and
`Adolescents With Bipolar Disorders
`'
`RA. Kn-watrb and :W.R Ddfidlu
`
`REVIEW
`Ps chopharmacologic Strategies for
`Y
`.
`-
`-
`the Treatment of Aggression ll"I Juveniles
`H. Steiner. K. Sauna, and K. Chang
`'
`
` E §
`
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`0- E E g :
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`www.onssp2:lIums.cnm
`-
`
`_
`
`CNS Specrrurns is an
`Index Medicus journal.
`
`"._
`'3
`’-
`
`x
`
`.__..e........_...j....—-.—v
`
`1
`-
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`1 of11
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`CNS SPECTRUlVlS®
`
`
`
`The international Journal of Neuropsychiatric Medicine
`
`Table of Contents
`
`
`
`By Neal D. Ryan, MD
`
`. fiEl/JEW
`
`2'38 Psychoph armacologic Strategies for the
`Treatment offilggression in _]uveniles
`
`By Hanssteiner, MD, Kirti Saxena, MD, and
`Kiki Chang, MD
`
`Volume 8 - Number It
`
`2115
`
`CNS Soectrums - April 2003
`
`2 of 11
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`April 2003
`Volume 8 - Number 4
`
`Feature Articles
`
`252 Introduction: The Psychopharmacol-ogic
`Axmanmentarium in the Pediatric Population
`'83: Karen Dineen Wagner, MD
`
`REVIEW
`253 Non-Stimulant Treatment of
`Attention-Deficit/Hyperactivity Disorder
`By Steven R. Pliszka, MD
`
`ORIGINAL
`
`S
`
`R
`
`259 Does Comorbid Attention-Deficit/Hyperactivity Disorder
`lmpact the Clinical Expression of
`Pediatric Obsessive—Compulsive Disorder?
`By Daniel A. Geller, MBBS, FRACP, Barbara Coffey, MD,
`Stephen Faraone, PhD, Lisa Hagermoser, BA, Noreen K.
`Zaman, BA, Co_lleen L. Farrell, BS, Benjamin Mullin, BA,
`and Joseph Biederrnan, MD
`
`'ClV1E-Accredited Articles
`
`fiEVl'§_W
`
`273 The Use ofl\’Iood Stabilizers and Atypical Antipsychotics in
`Children and Adolescents with Bipolar Disorders
`By Robert A. Kowatch, MD, and Melissa P. DelBello, MD
`
`REVIEW
`
`233 Medication Treatment for Depression in Children
`and Adolescents
`
`CNS Spettrums is an
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`and is available on MEDLINE
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`Neuropsychiatric Association
`with members in 30 countries.
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`is published monthly by
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`2 of 11
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`
`Review Article
`
`The Use of Mood Stabilizers and
`
`Atypical Antipsychotics in Children and
`Adolescents Witli Bipolar Disorders
`
`by Robert A. Kowatch, MD, and Melissa P. DelBeI|o. MD
`
`
`A BSTRA CT
`
`The clinical use ofmood stabilizers and antipsychotics in
`children oz-id adolescents with bipolar disorders has increased
`significantly over the pastfew -_vears. These agents have mul-
`tiple effects and interactions. This articles reviews the studies
`that support the use of mood stabilizers and atypical antipsy-
`cliotics in children and adolescents with bipolar disorders
`and presents information on these agents phonnacoltinetics,
`closing, and drug interactions.
`CNS Spectrurns 2003;8{4).'.?73-280
`
`'
`INTR OD l-;'§;Tl' ON
`The clinical use of mood stabilizers and antipsychotics
`in children and adolescents with bipolar disorders has
`increased significantly over the past few years. despite
`the fact that there are few controlled trials in this'popula-
`lion. Current clinical practice is to treat mood episodes in
`children and adolescents with bipolar disorders. much as
`one would adults with these disorders. using mood stabi-
`lizers and antipsychotics."-‘ It is also common clinical
`practice to have patients continue on medications for
`some time lollowing remission. although the optimal
`length of maintenance treatment remains unclear and
`available guidelines are based on limited consensus. no_t
`controlled trial outcomes. In this article, we will review
`the studies that support the use of mood stabilizers and
`atypical antipsychotics in children and adolescents with
`bipolar disorders.
`'
`
`MOOD SUDIBILIZIERS
`
`Several different classes of psychotropic agents have
`“mood stabilizing" properties including lithium. valproate.
`carliamazepine, and the newer atypical antipsychotic and
`antiepileptic agents. Ghaerni" recently proposed that for
`the treatment of bipolar disorders that a mood stabilizer is.
`“An agent with ellicacy in at least one ofthe three phases
`of bipolar tlisorcler (ocutemania. acute depression, or pro-
`phylaxis}. and it should not cause affective switch to the
`opposite mood stale nor should it worsen the acute
`
`episode.” This dclinition makes good clinical sense and is
`useful heurislically when discussing the various psy-
`chotropics that have mood stabilizing properties.
`
`Lithium
`
`_
`
`Lithium is the oldest mood stabilizer and has the most
`studies supporting its use for bipolar disorder in adults.
`Lithium administration has been shown to alter the post-
`receptor coupling of signal-transducing G-proteins.
`Through C-proteins, many neurotransmitter receptors are
`linked to the enzyme phospholipase C. which hydrolyzes
`the membrane phospholipid phosphatidylinositol biphos~
`phate to produce two-second messengers, diacylglycerol,
`and inositol triphosphate. Diacylglycerol activates protein
`kinase C. and inositol triphosphate releases calcium,
`which acts as a second messenger. Phospholipid phos-
`phatidylinositol biphosphate is synthesized from free
`inositol. However. lithium blocks inositol rnonophos-
`phatase. which inhibits neurons from generating free
`inositol. Therefore. lithium inhibits second messenger
`pathways.’-‘ Several controlled studies have clearly
`demonstrated lithiurn's efficacy in the treatment and pre-
`vention ol manic episodes in adults.‘ Therelhave been five
`controlled trials of lithium in‘ bipolar-disordered children
`and adolescents. Of these five studies. foui-3"‘ used a
`crossover design, which is a less than ideal design for an
`illness that is cyclical in nature. The average number of
`subjects in each of these studies was 18 and response
`rates ranged from 33% to 80%, which rellects the hetero-
`geneous samples and methods employed.
`ln the only well-controlled prospective. placebo-com
`trolled. investigation oflithium in children and adoles-
`cents with bipolar disorders {N=25]. Celler and
`colleagues" found that after 6 weeks of treatment, sub-
`jects treated with lithium showed a statistically signifi-
`cant decrease in positive urine toxico_logy_screens and a
`significant improvement in global assessment of function-
`ing (46% in the lithium-treated group versus 3% in the
`placebo group). in this study, the adtJlescent's diagnosis
`
`lilmrmclt L1 pro}.-5_cor I9’ p.\'_t'cltmI'I'ji' tmrl pediatrics nntl Dr. Delflello u wasuturit professor ofps)'t.'ltIu1r_v mid petltrrtrtcs,
`Dr.
`':"s}‘cltivtrr'_vnt Cinrintmti Cltilrlretti Hr.-.~'_m'tul .-l’leu‘icnl Center and at the L"nii::.-rrit_i' of Cills.-irmrui .-l‘!mlicm' Cs.-rm.-r in Ohio.
`Dt3t‘lr)sttres.' The rttrtlmrs rr_ntJrLr rlofintrncirtl, r:¢'nrt'-mtic, or rstlrer strppria-1 of this iyorlr.
`
`lmtll. In the Dcpurtritertt of
`
`.-l-ll). Cim.'imiuti Cltilrlrertit llrtxpitatl .-llerlicrul Center and The Uttim-rsit_v of Cirtcinrtrtti sllerlicxrl
`Plmre ilirect rill r.:.arre.t_pur|rle-rrcr: tn: llriliert .=l_ Krill-'ttll‘li.
`Critter. Dr-pirrtmcrtt of P.t_1't.'ltI‘-‘I!-"_\'.
`.-'|'l.‘lB 726}. El). Box 670559, Cincirltluti, OH -1526.7-0559; Tizl: 5J3-553-9953. Frat‘: 513-553-4305; E-mail.‘
`Robert. K.in'uh'lt @Itt'.ntlU.
`Volume 8 - Number a
`273
`(NS Spectrums - April 2003
`
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`' Review Article
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`
`of bipolar disorders preceded their substance abuse by
`several years. This study demonstrated the efficacy of
`lithium carbonate for the treatment of bipolar adolescents
`with comorbid substance use disorders, but did not mea-
`sure the effect of lithium on mood in these adolescents.
`Clinical Use
`
`Lithium is readily absorbed from the gastrointestinal
`system with peak levels occurring 2-4 hours after-each
`dose. Lithium is excreted by the lcidneys and its serum
`half-life in children and adolescents is estimated to be
`
`-l8 hours" Weller and colleagues“ ‘devised a lithium
`dosage guide for children and adolescentsbased upon
`body weight that is useful. accurate and easy to use with
`outpatients. According t-o these guidelines. a dose of
`30 mgt'lcgt'da_\- in three divided doses will produce a
`lithium level of 0.6-1.2 mEqfl_ within 5 days in 3
`6-12-year-old child. in children. lithium is usually admin-
`istered 2—3 timeslday and after an adequate serum level is
`reached. it may be administered once in the morning and
`once at bedtime in a controlled-release preparation. In
`adolescents, lithium may be administered once daily, usu-
`ally at bedtime, in a controlled-release preparation- Serum
`lithium levels in the range of 0.8-1.2 rnEq2'L are necessary
`for mood stabilization during treatment of a child or ado-
`lescents during a manic episode and it is best to measure
`serum lithium levels 12 hours after the last dose. it is
`important to understand that lithium has a very narrow
`“therapeutic window" and that lithium toxicity can. in
`fact. be seen at doses close to therapeutic levels. Possible
`side effects of lithium in- children and adolescents include
`
`weight gain, nausea, polyuria, ipolydipsia, tremor, acne,
`and hypothyroidism.
`Baseline studies prior to initiating treatment with
`lithium should include: general medical history and phys-
`ical examination; serum electrolytes; crcatinine. blood-
`urea nitrogen and serum calcium levels; thyroid function
`tests; Electrocardiogram (EKG); complete blood count
`. with differential; and a pregnancy test for sexually active
`females. Renal function should be tested every
`2-3 months during the first 6 months of treatment with
`lithium carbonate. and thyroid function should be tested
`during the first 6 months of treatment. Thereafter. renal
`and thyroid functions should be checked every 6 months
`or when clinically indicated.
`Chronic treatment with lithium can potentially cause
`hypoparathyroidism so serum calcium levels shouldbe
`checked once a year. Lithium should be administered
`cautiously and serum levels monitored carefully in
`patients with significant renal, cardiovascular, or thyroid
`disease. or severe dehydration. Drug interactions with
`lithium are common and patients should be advised not to
`take any other medications without first consulting with
`their prescribing physician.
`The following medications may increase serum lithium
`levels: antibiotics (cg. ampicillin and tetracycline). l"lOI't-
`steroidal anti-inflammatories (eg, ibuprofen). antipsy-
`chotic agents. propanolol. and selective serotonin
`reuptalce inhibitors {eg. fluoxetine)." Lithium should be
`administered cautiously and serum levels monitored care-
`fully in patients with significant renal. cardiovascular, or
`
`TABLE 1. MOOD STABILIZERS FOR BlP_0U'-\R CHILDREN AND ADOLESCENTS
`
`ttg Trade
`_ blame
`Carbamnzepine
`Tegrctol
`Carbamazepine XR Tegretol XR
`
`Hgw fiuggligd tmgi gaging Dgsg
`100. 200
`Oulpat.ienLs:
`-100. 200, 400
`'1' mgfltgfday
`2-3 daily doses _
`
`o
`
`Tar
`Based on
`response and
`serum levds
`
`Therapeutic
`figrum Lgvgl
`3-11 mg/L
`
`I..ill‘tim1t
`l.ill'tit..It'I't
`Lilltiunt
`
`Lithobirl
`Eskalith
`Cibalith-5
`
`300 (and 150 generic)
`300 or 450 CR
`Lithium 5 cc=3D0 mg
`
`Outpatients:
`25 mglltgfday
`2-3 daily doses
`
`30 mgfltyduy
`2-3 daily doses
`
`0.3-1.2 msqrt;
`
`Oxeatbuzepine
`
`Trileptzd
`
`150. 300. we
`
`150 mgBlD
`
`Depak ene
`Val prnic rl. t.'lt.'l
`Dit-atltirm-.:t .‘3ot]ittm Depult-ole DR
`Depkt ttt: E R
`
`250, syrup
`I25. 250. 500
`250. 500
`
`Outpatients:
`I5 mg/'kg’da_\'
`2—~3 tlttily dunes
`
`20-29 kg,
`900 mgfdoy
`30-39 lag
`L200 mytltly .
`>39 kg
`l .300 ttigfduy
`
`20 mg/It gy/tluyi
`2-3 daily doses
`
`gaugiong
`Monitor for CYP
`dntg interactions
`
`Monitor for
`hypothyroidisrn
`Avoid during
`pre gnnn c 3!
`
`Monitor for
`h_\-'ponatremia
`
`90-22:} ntgfl,
`
`Monitor liver
`functions and for
`puncreatitis
`Avoid during
`pregiiancy
`
`US=\..|nited States: CYP=cy‘tochrt:me Past}; XR=eit‘terIded-release: Li=|ilhiuI'n.' (R=t:ontrorted-release; NtA=not applicable; DFt=delayed~tetease. EFl=e:t1endeo-release.
`Kowatth RA, DetBel1o MP. CNS Spectrurns. Vol 5. No 41. 2003.
`
`Volume 8- Number it
`
`274
`
`CNS Spectrum: - April 2003
`
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`Review Article
`
`
`thyroid disease, or severe dehydration. .-\dequatc_birth
`control measures must be followed in females of child-
`bearing age taking lithium as lithium IS associated Wtll't
`an increased rate of cardiac abnormalities.”
`Table 1 lists .the pediatric dosages, ‘target serum levels.
`side effects, and cautions for some of the mood stabilizers
`discussed in this article.
`
`valp roa to
`Valproate is another mood stabilizing agent which has.
`_clen-ionstrated efficacy in adults with bipolar disorders.'‘-‘'’
`It is a simple branched-chain carboxylic acid, which was
`first introduced in the United States in 1978 as an
`antiepileptic agent. \*'alproate’s exact mechanism of action
`in mood disorders is unclear but appears to involve
`increased turnover of the inhibitory neurotransmitter
`‘}'—aminobutyric acid (GAB.-\) with potentiation of
`CAB.-\er'gic functions. blockage of cell firing induced by
`tV-methyl-D-aspanate-type glutamate receptors. and atten-
`uation of protein kinase C isoenzymes.”-"‘
`A review of the five adult controlled valproate studies for
`the acute treatment of mania showed an average response
`rate of 5-’l-‘7c." ln many of these studies, positive results
`were obtained even though patients wereisclected from a
`population previously refractory to lithium treatment and
`those characterized by rapid cycling, mixed affective
`states, and irritability. There have been a number of older
`case reports and open prospective trials of valproate in
`children with bipolar disorder and adolescents suggesting
`its effectiveness."'”
`Recently, there have been two prospective trials that
`have also suggested that valproate may be effective in this
`population. Kowatch and colleagues“ compared the effi-
`cacy of three mood stabilizers. lithium, valproate, and Car-
`bamazepine in the acute phase treatment of bipolarl or [1
`children and adolescents during a mixed or manic episode.
`In this study, 42 outpatients with a mean age of ll.4 years
`were randomly assigned to 6-8 weeks of open treatment
`with either lithium, valproate, or carbamazepine The pri-
`mary efficacy measures were the weekly Clinical Global
`lmpression (CCl]-lmprovement score and the Young Mania
`Rating Scale (Y-MRS). Using a >S0% change from base-
`line to exit in the Y-MRS scores to define response, the
`response rates were: 38% for carbamuzepine, 38% for
`lithium, and 53% for valproate (x9=0.B5, P=.60). "Each of
`the three mood stabilizers were well tolerated and no seri-
`ous odveise effects were seen.
`
`Wagrter and colleagues“ have recently published the
`results of an open~l-abel study of valproate in -'-l0 r:li_ildrcn
`and adolescent-.= (?—l9 years of age) with a primary rliag- .
`n_osis of bipolar disorders. This stutly attempted to follow
`an openltliscuntinitiation design in which all the patients
`were started on rnetlication and wt-,-re then randoniizetl to
`
`either placebo or to inetlication whr-:n,tltey improved, but
`too few subjects participntetl in the dou hie-blind period to
`allow for statistical analysis of t-.-ffit.-ar:_v. In their initial
`
`open-label phase, subjects were given a starting dosage of
`valproate of 15 rngfltgfday. The mean final dosage was
`1? inglltgfday. Twenty-two subjects l_55%) showed a
`50% or more improvement in Mania Rating Scale (MRS)
`scores during the open phase of treatment. Wagner and
`colleagues" concluded that this study provided "prelimi-
`nary support for efficacy and safety of divalproex in the
`treatment of acute manic and mixed states of bipolar dis-
`order in children and adolescents."
`
`Clinrral Use
`
`Valproate is readily absorbed from the gastrointestinal
`system with peak levels occurring 2-4 hours after each
`dose. But, if valproate is given with meals to decrease nau-
`sea, then peak levels may be reached in 5—6 hours.
`Valproate is highly protein bound, metabolized in the liver
`and has a serum half-life between 8-16 hoursin children
`
`and young adolescents.“ A starting dose of valproate of
`15 mg/kg/day in 2-3 divided doses in children and adoles-
`cents, will produce serum valproate levels in the range of
`50-60 mg/n1L. Once this low serum level has been
`obtained, the dose is usually titrated upwarcls depending
`upon the subject's tolerance and response and it is best to
`measure serum valproate levels 8-12 hours after the last
`dose. Optimum serum levels among manic adults is‘
`between 75-110 n-igi'mL.’*‘ A starting dose of valproate of
`15 mgfkyday in 2-3 divided doses in children and adoles-
`cents, will produce serum valproate levels in the range of
`50-60 mg/mL. Once this low serum level has been obtained
`the dose is usually titrated upwards depending upon the
`subject's tolerance and response and it is best to measure
`serum valproate levels 3-12 hours after the last dose.
`Baseline studies prior to initiating treatment with val-
`proate should include general medical history and physical
`examination; liver function tests; complete blood count with
`differential and platelets; and a pregnancy test for sexually
`active females. A complete_ blood count with differential,
`platelet count, and liver functions should be checked every
`6 months, or when clinically indicated. Possible common
`side effects of valproate in children and adolescents include
`nausea, increasediappetite, weight gain, sedation, thrombo-
`cytopertia, transient hair loss, tremor, and vomiting. Rarely,
`pancreatitis and liver failure can also occur. Valproate is
`metabolized in the liver by the cytochrome P450 (CY?) sys-
`tem and has interactions with a number of other medica-
`
`tions which also are metabolized by this system.
`Medications that will increase valproate levels include
`erythrornycin. selective serotonin reuptake inhibitors, cime-
`tidine. and salicyl-ates. Valproate may increase the levels of
`the following medications: phenobarbital, pi-imidone. carbo-
`mazepinc, phenytoin. tricyclics, and lamotr'igine_ V-alproate
`should be aclrninistercd cautiously and serum levels and
`liver functions monitored carefully in patients with signifi-
`cant liver dysfunction. slitleqtiute bit1h-control rneasures
`must be followed in adolescent females taking valproate is
`associatecl with an increased rate of neural tube defects.
`
`Volume 3 - Number it
`
`275
`
`CNS Spectrurns - April zoos
`
`5of11
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`There has been a recent concern regarding the possible
`association between valproate and pol}-cystic ovarian syn-
`drome IAPCOS). The initial reports of PC05 were in women
`with epilepsy who were treated with divalproex.“ One
`hypothesized mechanism for valproate induced PCO5 is
`that obesity secondary to valproate results in elevated
`insulin levels, which leads to increased androgen levels and
`ultimately P_C05."" 0'Donot-an and colleagues” recently
`reported that rates of menstrual irregularities and PCOS
`were higher in women with bipolar disorder who were taking
`valproate than in those wl'to were not taking valproate and a
`Comparison group of healthy volunteers.
`A recent review of the reproductive safety of psychotrop-
`ics by Ernst and Goldberg“ commented that. "the current
`data do not appear conclusive enough to contraindicate the
`use of valproate.“ They recommended that females treated
`with valproate undergo the following; a weightibotly mass
`index prior to treatment with valproate and at- each follow-
`up visit; baseline assessment of menstrual cycle patterns
`and monitoring for irregularities; baseline and annual lipid
`profiles. lf a female patient treated with valproate develops
`hirstitism, alopecia or acne, they should be referred to an
`endocrinologist for a further work-up for PCOS.
`
`Carbamazepine
`Carbarnazopine is an anticonvulsant that is structurally
`similar to imipramine and that was first introduced in the
`US. in 1963. There have been no controlled studies of car-
`
`bamazepine for the treatment of children and adolescents
`with bipolar disorder, and the rnajority of reports in the liter-
`ature concern its use in children and adolescents with atten-
`
`tion-deficitlhyperactivity disorder {ADHD) or conduct
`disorder some of whom also had neurolog-ic disorders.'“"'
`Flea]: and colleagues“ reported the worsening of behavior in
`6 of 20 child and adolescent patients treated with carbo-
`- mazepine for ADHD and conduct disorder.
`Carbamazcpine is metabolized by the CYP hepatic sys-
`tem to an active metabolite. carabarnazepine-10,11~epox-
`ide. C-arbamazepine induces its own metabolism and this
`“autoinduction" is complete 3-5 weeks after starting 3 fixed
`dose. Initial carbamazepine serum half-lives range from
`25-65 hours and then decrease to 9-15 hours after autoin-
`
`duction of the CT? enzymes.
`Clinical U_se
`
`OIHER MOQD S'II4Bl'LIZl'NG 2-lGE.NT_S_
`There have been several new antiepileptics that have
`been developed for the treatment of epilepsy that my have
`mood stabilizing properties. Data are presently limited
`regarding the efficacy and tolerability of these agents for the
`treatment of pediatric bipolar disorder. However, they are
`probably useful as adjuncts for the treatment of acute affec-
`tive episodes. There have been several reports of lan1otr'ig-
`ine as adjunctive treatment for children and adolescents
`with bipolar disorder.” However. it use for pediatric bipolar
`disorder has been limited due to the risk of potentially
`lethal cutaneous reactions. such as Stevens-Johnson syn-
`drome and toxic epidermal necrolysis. The risk of a serious
`rash is -2-3 times greater in children and adolescents
`<16 years of age compared with adults but a recent more
`conservative dosing schedule appears to have substantially
`reduced the rate of serious rashes.“-*3 The more common
`side effects of lamotrigine are dizziness, tremor, sornno-
`lence. nausea. asthenia, and headache.
`There has been one case report suggesting that
`gabapentin may be useful for the treatment of adolescent
`mania. however. further controlled studies in children and
`adolescents with bipolar are necessary.“ Doul-.tle—blincl
`placebo—controlled studies of gabapentin have demon-
`strated that gabapentin is no more effective than placebo
`for the treatment of acute mania in aclults." However,
`-gabapentin appears efficacious for the treatment of anxiety
`disorders in adults“-“' and is generally well tolerated in
`childrenanrl adolescents. Therefore, gabapentin may be
`particularly useful for treating children and adolescents
`with bipolar disorder who are also diagnosed with a comer-
`bid anxiety disorder.
`_
`Preliminary data from open studies suggest that topira-
`In patients 6-12 years of age. a reasonable starting, dose
`mate may be effective as an adjunctive treatment for pedi-
`ofcarbarnazapine is 100 mg BID and in patients aged
`l2 and older, 100 mg TlD. Serum level of carbarnazepine
`atric bipolar disorcler,” although more
`recent
`double-blind, placebo-controlled studies in adult with
`between 3-11 mg/ml. are necessary for seizure control. The
`mania suggest, that as monotherapy, it is no more effective
`niaxin-mm daily dose of carbamazepine should not exceed
`than placebo. Word-finding difficulties have been reporteé
`L000 lT'Ig.fl:lt‘t}'
`in t:_l'til(.l'ren ages 6-12 years antl
`in tip to one third of patients treated _\vith topiramate.’
`L200 mg/day in patients .213 years of age. Possible com-
`Topirnm-ale is associated with anorexia and weight loss,“
`mon sitle_effects of carbamazepine in children and adoles-
`and therefore, may be useful as acljunctive. treatment fl)
`cents inclttde sedation. ataxia, tliniriess. blurred vision,
`children and adolescents with bipolar disorder \\‘ ho hav-
`nau.-tea, and vomiting.
`gainetl weight as a result of treatment with other psy
`Baseline Ettttlies prior to initiotiitg treatment with ca1'bu—
`chotropics. Preliminary data suggest that other no‘
`niazepine should include a general medical history and
`
`Volume 5 - Number :1
`2}'5
`
`Review Article
`
`
`physical examination, complete blood count with differen-
`tial. liver function tests and a pregnancy test for sexually
`active females. Because of its stimulation of the hepatic
`CY? system, carbamazepine has many clinically significant
`drug interactions in children and
`adolescents.
`Carbamazepine decreases lithium clearance and increases
`the risk oflithium toxicity. Medications that will increase
`carbamazepine levels include erythromycin, cirnetidine,
`fluoxetine. verapamil and valproate. Carbamazepirie may
`increase the levels of the following medications: phenobar-
`bital, primidone, pl'tB1"I_Vt.Oit't._ tricyclics, and lamotn'gine."
`
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`antiepileptics. including Iiagabine, oxcarbainazepine. lev-
`etiracetam. and aonisamtde, may also be useful as
`adjuncts for treating adults with mania. However. there are
`pre:-zentlv no reports of thes.e medications for the treatment
`of children and adolescents with bipolar disorder.
`
`.-‘ITYPICAL A.-\"T.lPS}"CHOTICS:
`
`more energy; pressured speech; grandiosity; racing.
`thoughts; overt anger; poor judgment; and lack of insight.
`The mean change in MRS score from baseline was
`-14.8 for the valproate group and —1?.?. for the olanzap-
`ine group after 3 weeks of treatment. The authors reported
`that there was no statistically significant difference seen
`in efficacy measured by the MRS between the two groups
`and that the valproate-treated patients had significantly
`less weight gain than the olanzapine patients. Both val-
`proate and the atypical antipsychotics appear to be effica-
`cious in the treatment of the manic phase of adult bipolar
`disorder. with the atypical antipsychotics having a slightly
`greater efficacy. but also causing more weight gain and
`sedation. which are significant problems in children and
`adolescents with bipolar disorders.
`
`The atypical antipsychotics are very powerful psy-
`chotropics that have recently been found to be eflicacious in
`the treatment of adults with schizophrenia and acute bipolar
`mania.“-"5 The atypical antipsychotics differ from typical
`antipsychotics in their “limbic-specific" dopamine type-
`2-receptor binding and high ratio of serotonin rype-2-recep-
`tor binding to dopamine type-2 binding.“ These atypical
`agents not only have antipsychotic activity but may also
`ATYP1C.atL‘ANTl'PSYCHOTl’CS: CHILD AND
`possess thymoleptic properties with favorable effects on the
`ADOLE.',SCENT BIPOLAR DISQRDER .5] QDIQS
`depressive and manic symptomsof patients with bipolar
`There have been several recent case series and open-
`disorders.“ To date. there have been three large controlled
`labelreports suggesting that atypical antipsychotics. such
`studies of olanzapine.-"“ and tvvo controlled trials“-“‘ of
`as clozapine.“ risperidone.“ olanzapine“"*“”‘ and quetiapine,”
`risperidone in the treatment of adults with bipolar disorders.
`are effective in the treatment of pediatric bipolar disorder.
`All of these studies found these atypical agents to be ef.fica-
`In a retrospective case seriesof severely ill children and
`cious for the treatment of bipolar disorders.
`adolescents (50% of whom were diagnosed with bipolar dis-
`There have been two direct comparison trials of olan-
`order). Kowatch and colleagues“ found that CG1-Severity
`zapine versus valproate in adults with bipolar disor-
`ratings significantly improved from baseline to endpoint,
`ders."-"" Both studies had a 3-week. double-blind. acute
`suggesting that atypical antipsychotics may be effective for
`phase. that examined the efficacy of valproate and olanza-‘
`the treatment of pediatric bipolar disorder. Most patients in
`pine for acute mania in adults. In a multisite study by
`this study were receiving concomitant medications.
`Tohen and colleagues,“ 251 adult inpatients with mania,
`In another retrospective chart review of outpatients
`were randomized to double-blinded treatment with alan-
`(N228). Frazier and colleagues“ investigated the effective-
`zapine or valproate for 3 weeks. The study consisted of a
`ness and tolerability of the risperidone for the treatment of
`3-week acute-phase study followed by a 44-week exten-
`pediatric rnania.The authom preformed CC} with separate
`sion period. The mean dose of olanzapine was
`assessments of mania. psychosis. aggression. and ADHD.
`16 mg/day: the mean dose of valproate was 1.584 mg/day.
`These children received a mean daily dose of 1.‘r:t1.3 mg
`The study‘s primary efficacy measure was the Y-MRS.“
`over an average period of 6.1:8.5 months. Using a
`and remission was defined by study protocol as a Y-MRS
`CGI—lrnprovement score of£2 {very muchhnuch improved)
`is 512. There were no significant differences in study
`to define robust improvement. 82% showed improvement
`completion rates between olanzapine-' (68.8%) and dival-
`in both their manic and aggressive symptoms, 69% in psy-
`proes-treated patients (64.3%). Clinical response based
`chotic symptoms. but only 8% in ADHD symptoms.
`on a 50% Y-VIRS improvement at endpoint was achieved
`Although this study is limited by its retrospective nature.
`in 54% of olanzapine-treated patients compared to
`these data suggests that risperidone may be effective for
`-=l2% of valproate-treated patients. The most common
`the treatment of pediatric mania.
`treatment-emergent adverse events associated with olan-
`Several case series and reports have indicated that
`zapine were somnolence. dry mouth and increased
`olanzapine, which has a similar receptor profile to clozap-
`appetite while the most common associated with valproate
`inc. may be useful for the treatment of mania associated
`was nausea. The authors concluded that the olanzapine-
`with pediatric bipolar disorder.“'"" However. these most of
`treated patients had superior mania improvement than
`these reports are retrospective and the total number of
`those on divalpruex. as rated by the Y-WIRS.
`subjects is small (N211). In a more recent study. Frazier
`Zajecka and colleagues“ randomized 1'20 adult inpa-
`and colleagues” reported the effectiveness and tolerability
`tients with bipolar disorders to either valproate {n=63) or
`of olanzapine for the treatment of acute rnania in children
`olanzapine t_n=5T) in a double-blinded. 21-day treatment
`and adolescents. The study was an 3-week open-label
`period. Treatnient with valproate was initiated at
`prospective study of olanzapine monotherapy-(dose range:
`20 nigtkg/clay anti olanzapine was initiated at l0 mg/clay.
`2.5—'.?0rngfday) for the treatment of 23 children and ado-
`The primary efficacy measure was the t\'lfiS, which is an
`lescents with bipolar disorder. West [22 out of the '23) of
`11-item measure of the core symptoms of mania. includ-
`the patients completed the study. Olanzupine treatment
`ing elevaterl mood; increased t.t(:ll\-'it_t':_ less need for sleep;
`
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`was associated with significant improvement in Y-MRS
`score. Using a predefined criteria for improvement 3-30‘7a
`decline in Y~MRS and a CG]-Severity mania score <3 at
`endpoint, the overall response rate was 61%. Overall.
`olanzapine was fairly well tolerated, however, body weight
`increased significantly during the 8-week study.
`lt has recently become apparent that ziprasidone and
`several other antipsychotic agents can prolong the QT
`jmen-a] (QT.-g}, which could potentially cau