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Service de psychiatrie de lenfant et de ladolescent, hopital Pitie-Salpetrie`re, universite Pierre et Marie-Curie, 47-83, boulevard de lHopital, 75013 Paris,
France
b
CNRS UMR 7222, institut des syste`mes intelligents et robotiques, universite Pierre et Marie-Curie, place Jussieu, 75005 Paris, France
I N F O A R T I C L E
R E S U M E
Historique de larticle :
Disponible sur Internet le 25 fevrier 2014
La pharmacologie dans les troubles bipolaires chez lenfant et ladolescent benecie dun interet
croissant mais peu detudes concernent le lithium. Lefcacite du lithium en monotherapie est moderee,
avec des taux de reponse de lordre de 35 a` 63 %. Le benece des combinaisons therapeutiques
(association au divalproate de sodium, a` la carbamazepine ou a` la risperidone) est net avec des taux de
reponse atteignant 70 a` 90 %. Le taux de rechute sous lithium en monotherapie est eleve (37 a` 56 %) mais
peu etudie. Si le prol de tolerance du lithium est rassurant, les effets secondaires rapportes semblent
plus frequents que chez ladulte, et lon ne dispose daucune donnee a` long terme. Enn, la lisibilite de
tous ces resultats souffre dune limite majeure liee a` lheterogeneite clinique avec lusage extensif du
diagnostic de bipolarite chez lenfant prepube`re. Les etudes futures benecieront du cadre diagnostique
distinguant les diagnostics de Dysregulation Emotionnelle Seve`re (ou Temper Dysregulation
Disorder with Dysphoria dans le DSM-5) chez lenfant et de trouble bipolaire de type I chez ladolescent.
2014 Elsevier Masson SAS. Tous droits reserves.
Mots cles :
Adolescent
Benece therapeutique
Enfant
Posologie
Revue de la litterature
Sel de lithium
Trouble bipolaire
A B S T R A C T
Keywords:
Administration and dosage
Adolescent
Bipolar disorder
Lithium citrate
Mania
Review of the writing
Therapeutic benet
Bipolar disorder in youths is a severe psychiatric disorder that potentially results in high-relapse rates
and disrupts the normal psychosocial development. Many adults with bipolar disorder identify the onset
of their symptoms in childhood and adolescence, indicating the importance of early accurate diagnosis
and treatment. The lifetime prevalence is estimated in adolescence at 0.1% for bipolar I disorder and 1%
for all bipolar spectrum disorders. Classic bipolar disorder with well-delineated episodes is rare among
prepubertal children. The treatment of bipolar disorder in youths raises challenges and difculties.
Lithium is recommended as one of the rst-line treatment options of bipolar disorder in children and
adolescents with FDA approval as early as 12 years. Lithium prescription is approved in France for
bipolar disorder only for adolescents older than 16 years old. This comprehensive literature review
incorporates research studies evaluating the effectiveness of lithium in children and adolescents with
pediatric bipolar disorder (randomized controlled trials, open-label studies and retrospective chart
reviews). Lithium was evaluated as a monotherapy, as well as part of a combination treatment, in the
acute and maintenance phases. The effectiveness of a lithium monotherapy is moderate with response
rates of approximately 35 to 63%. Its efcacy is similar to valproate and carbamazepine; however,
lithium appears to be superior in case of psychotic symptoms. A recent study reported the superiority of
risperidone over lithium in bipolar mania with a comorbid attention-decit/hyperactivity disorder.
While it is ideal to use the lowest possible dose of monotherapy medication to decrease adverse side
effects, most patients require adjunctive medication treatment for the stabilization of bipolar symptoms.
Data suggest that a combined treatment with lithium (using valproate, carbamazepine or risperidone)
may provide a better remission of symptoms, with response rates between up to 70 and 90%. The relapse
rate in lithium monotherapy is high (37 to 56%); nevertheless, very few studies have measured the longterm effects of the medication in pediatric bipolar disorder. The data from the available pharmacological
studies need to be interpreted cautiously because of the controversy surrounding the denition and
* Auteur correspondant.
Adresse e-mail : david.cohen@psl.aphp.fr (D. Cohen).
0003-4487/$ see front matter 2014 Elsevier Masson SAS. Tous droits reserves.
http://dx.doi.org/10.1016/j.amp.2014.02.001
220
diagnosis of bipolar disorder in youths. The continuity between childhood-onset bipolar disorder and the
current adult-oriented DSM-IV criteria in adolescence is currently debated. The diagnostic framework
has evolved to distinguish the diagnoses of Severe Emotional Dysregulation (or Temper Dysregulation
Disorder with Dysphoria in DSM-V) in children from bipolar I disorder in adolescents. Research samples
often include both of these clinical pictures. This heterogeneity in the patient population introduces a
major caveat towards the interpretation of the available literature addressing treatment strategies. The
distinction between these two forms is even more relevant given the fact that preliminary studies have
shown various clinical courses, family psychiatric histories, different prognoses, as well as therapeutic
responses. Even if the safety prole of lithium is reassuring, the reported side effects seem to be a more
frequent in youths than in adults, especially if the child is young. The most commonly reported (> 20%)
adverse events were nausea/vomiting, diarrhea, abdominal pain, headache, dizziness, tremor and
pollakiuria. Weight gain and acne are side effects that are perceived to be particularly shameful during
adolescence. No data on long-term side effects are available. The limited studies examining the
pharmacokinetics of lithium may indicate the need for vigilance in the variability induced by the weight
in pediatric patients. Very few studies have examined predictors and moderators in the treatment of
bipolar disorder in children and adolescents. Being younger or suffering from comorbid attention-decit/
hyperactivity disorder have been associated with a poorer response to lithium. The aims of future
researches in bipolar disorder in youths may establish some evidence-based strategies for lithium
especially: (i) by examining the acute efcacy in mania and also in bipolar depression with a particular
attention to age-specic aspects and diagnosis at inclusion, (ii) by investigating the long-term
effectiveness of lithium treatment, (iii) by characterizing the long-term safety of lithium, (iv) by
identifying pretreatment variables associated with the effectiveness and tolerability of lithium, (v) by
studying adherence concerns in adolescents.
2014 Elsevier Masson SAS. All rights reserved.
1. Introduction
Le trouble bipolaire chez lenfant et ladolescent fait lobjet dun
interet grandissant depuis vingt ans. La severite, la chronicite,
limpact psychosocial de la maladie bipolaire au sein de cette
tranche dage sont tre`s souvent majeurs. Il apparat primordial que
des schemas therapeutiques securises et efcaces soient elabores
et evalues dans cette population specique. Le lithium est une
option therapeutique chez ladulte bipolaire depuis plus de
cinquante ans, reconnue pour son efcacite, avec un mode de
surveillance bien etabli. Sa prescription en population pediatrique
sest faite initialement en miroir de celle chez ladulte.
Avant daborder la prescription du lithium dans le trouble
bipolaire du sujet jeune, il est primordial devoquer les
controverses actuelles sur la symptomatologie bipolaire de
lenfant, et de presenter brie`vement ce qui apparat dans la
nouvelle nomenclature comme des phenotypes intermediaires
a` ne pas confondre stricto sensu avec le trouble bipolaire. Dans un
deuxie`me temps, nous presenterons les etudes sur lefcacite du
lithium dans le trouble bipolaire de lenfant et de ladolescent, tant
en phase aigue quen prevention de la rechute thymique.
Lidentication des facteurs predictifs (ou moderateurs) de la
reponse au lithium est essentielle an dimaginer un traitement a`
lavenir plus personnalise. Enn, une dernie`re partie sera
consacree aux premie`res etudes de pharmacocinetique en
population pediatrique ainsi qua` sa tolerance chez lenfant et
ladolescent.
221
Tableau 1
Symptomes maniaques chez lenfant et ladolescent : entre Severe mood dysregulation (SMD) et phenotype etroit [5].
Symptomes maniaques de lenfant
Severe mood dysregulation
Chronique et continu
Comorbidite elevee avec le TDAH
Symptomes psychotiques exceptionnels
Antecedents familiaux tre`s varies
Facteurs environnementaux au premier plan et troubles des apprentissages
frequents
Evolution troubles depressifs, borderline, trouble bipolaire II ou III
Episodique
Antecedents de TDAH marginaux
30 a` 60 % de symptomes psychotiques
Antecedents familiaux de bipolarite
Fonctionnement premorbide souvent de bonne qualite
Evolution trouble bipolaire classique , transition trouble
schizo-affectif ou schizophrenie
222
SMD
Carences
prcoces
Facteurs
prinataux
MANIE
Contexte
mais aussi Manie
inscrit dans maladie
mentale
Contexte
Facteurs sociaux
Apprenssage
Bb
Enfant
Adolescent
Adulte jeune
Fig. 1. Une vue developpementale de lhyperthymie chez lenfant et ladolescent : du Severe Mood Dysregulation (SMD) chez lenfant a` la manie typique chez ladolescent
[5].
Tableau 2
Etudes defcacite du lithium dans le traitement du trouble bipolaire de lenfant et de ladolescent (19952013) : en phase aigue en monotherapie (A), en traitement combine (B) et dans la prevention de la rechute thymique (C).
Auteurs (annee)
Design detude
Duree
Traitement
Crite`res dinclusion
Echelle pour
mesure
principale
Resultats
Ref.
n = 25
1218 (moy 16,3)
BP I, BP II, depression si
risque predictif de
bipolarite + addiction
CGAS
Taux de reponse :
Li = 46,2 % vs Placebo = 8,3 % (p < 0,05)
[21]
Li vs Placebo
n = 40
1218 (moy 15,2)
BP I (maniaque)
repondant au Li
YMRS
Taux de rechute :
Li = 52,6 % vs Placebo = 61,9 % (NS)
[29]
Randomisee controlee
double insu
8 semaines
Li vs Dvp vs Risp
Pas de groupe placebo
BP I (maniaque ou mixte)
Comorbidite TDAH
(92,8 %) et TOP (90 %)
CGI-BP-IM
Taux de reponse :
Li = 35,6 % vs Risp = 68,5 % vs Dvp = 24 %
Risp > Li (p < 0,001)
Risp > Dvp (p > 0,001)
Pas de difference signicative Li vs Dvp
[22]
Ouverte prospective
4 semaines
Li antipsychotiques
n = 100
1218 (moy 15,2)
BP I (maniaque ou mixte)
YMRS
Taux de reponse : 63 %
Taux de remission : 26 %
[27]
Ouverte prospective
(randomisation pour
dosage)
8 semaines
Li
3 dosages differents
n = 61
717 (moy 12,6)
BP I (maniaque ou mixte)
YMRS
CGI-I
Taux de reponse : 58 %
Pas de difference des differents dosages et
strategies dadministration
[16]
Ouverte prospective
6 semaines
Li
n = 27
1218 (moy 15,6)
BP I (depressive avec ou
sans symptomes
psychotiques)
CDRS-R
Taux de reponse : 48 %
Taux de remission : 30 %
[40]
Ouverte prospective
6 semaines
Li
n = 50
1317
BP I
CGI
Taux de reponse :
Debut a` adolescence = 80 %
Debut pre-pubertaire = 40 %
[49]
Ouverte prospective
4 semaines
Li
n = 60
30 avec TDAH
30 sans TDAH
1317 (moy 15)
BP I (maniaque)
Comorbidite TDAH
BRMS
Taux de reponse :
BP sans TDAH = 80,6 %
BP + TDAH = 57,7 % (p = 0,0005)
[48]
Ouverte prospective
randomisee (par
minimisation)
6 semaines
Li vs Dvp vs Cbz
Pas de groupe placebo
n = 42
818 (moy 11,4)
BP I, BP II (maniaque ou
mixte)
YMRS
[32]
Retrospective
10 ans
Li ou Cbz ou Dvp ou
APA ou combinaison
n = 75
1220 (moy 15,7)
BP I (maniaque ou mixte)
DIGS
[8]
Retrospective
6 ans
Li vs Dvp vs APA
YMRS
[38]
Retrospective
7,5 ans
Li vs Dvp
n = 42
1219
BP I (maniaque ou mixte)
Comorbidite TDAH
CGI-BP
Taux de reponse :
BP sans TDAH = 92 %
BP avec TDAH = 57 % (p = 0,007)
Pas de difference entre Li et Dvp
[47]
223
224
Tableau 2 (Suite )
Auteurs (annee)
Design detude
Duree
Traitement
Crite`res dinclusion
Echelle pour
mesure
principale
Resultats
Ref.
n = 90
517 (moy 12)
BP I, BP II (maniaque,
hypomane ou depressive)
67 % avec cycles rapides
YMRS
[18]
Ouverte
8 semaines
n = 38
517 (moy 10,5)
BP I, BP II (maniaque ou
hypomane)
comorbidite TDAH
mediques par
psychostimulants (66 %)
YMRS
[19]
Ouverte
6 mois
Li vs Dvp vs Cbz
pendant 68 semaines
Puis en association
Li + Dvp vs Li + Cbz vs
Dvp + Cbz
n = 35 (dont 20 nonrepondeurs
necessitant bitherapie)
718 (moy 11,4 3)
BP I, BP II (maniaque,
mixte, hypomane)
Comorbidite TDAH (80 %)
YMRS
[31]
Ouverte
1 an
Li monotherapie
Puis Li + Risp (chez
non-repondeurs a`
monotherapie par Li
pendant 8 semaines)
n = 38 sous
monotherapie Li, dont
21 non-repondeurs
sous Li + Risp
417 (moy 11,4)
BP I a` debut prescolaire
(avant 5 ans) (maniaque
ou mixte)
YMRS
[42]
Ouverte
6 mois
Li + Risp vs
Dvp + Risp
n = 37
518 (moy 12,1)
BP I (maniaque ou mixte)
Comorbidite TDAH (78 %)
YMRS
Taux de reponse :
Li + Risp = 82,4 %
Dvp + Risp = 80 % (NS)
[41]
Ouverte
4 semaines
Li+ antipsychotique
(Haloperidol ou Risp
ou quetiapine ou
thiothixene ou
olanzapine ou
chlorpromazine)
n = 35
1218 (moy 15,8)
BP I (maniaque ou mixte)
YMRS
Taux de reponse : 64 %
[28]
n = 60
517 (moy 10,5)
BP I, BP II
YMRS
CDRS-R CGAS
[20]
Ouverte prospective
6 mois (moy
14,9 semaines)
Li si reponse partielle
APA ou Dvp ou
psychostimulants
n = 41
717 (moy 11,8)
BP I
YMRS
[15]
Ouverte prospective
18 mois
Li
n = 37
1317
BP I
Rechute clinique
[50]
Ouverte prospective
5 ans
Li carbamazepine
frequent
n = 54
1317 (moy 16)
BP I
Rechute clinique
Taux de rechute : 44 %
[51]
Ouverte prospective
1 an
Li ou Dvp ou Cbz
n = 31
1418
BP I + comportement
delinquant seve`re
Nombre dactes
delinquants
[9]
APA : antipsychotique atypique ; BP I : trouble bipolaire de type 1 ; BP II : trouble bipolaire de type 2 ; BP Nos : trouble bipolaire non specie ; BRMS : BechRafaelsen Mania Scale ; Cbz : Carbamazepine ; CDRS-R : Childrens Depression
Rating Scale-Revised ; CGAS : Childrens Global Assessment Scale ; CGI : Clinical Global Impressions ; CGI-BP : Clinical Global Impressions for Bipolar illness ; CGI-BP-IM : Clinical Global Impressions for Bipolar illness ImprovementMania ; CGI-I : Clinical Global Impressions-Improvement ; DIGS : Diagnostic Interview for Genetic Studies ; Dvp : divalproate de sodium ; Li : Lithium ; NS : non signicatif ; TDAH : Trouble decit de lattention/hyperactivite ; Risp :
Risperidone ; YMRS : Young Mania Rating Scale.
225
226
[5]
5. Synthe`se et conclusion
[6]
[4]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
ts
Declaration dintere
[24]
[25]
[26]
[27]
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