+
Bipolar disorder
in children and adolescents
a valid clinical entity?
Alessandro Zuddas
Centro Terapie Farmacologiche in
Neuropsichiatria dell’Infanzia e dell’Adolescenza
Sezione di Neuroscienze e Farmacologia Clinica
Dipartimento di Scienze Biomediche,
Università di Cagliari
Clinica di Neuropsichiatria infantile
Azienda Ospedaliero-Universitaria di Cagliari
+ Bipolar disorder
in children and adolescents
n 
Diagnostic boundaries still matter of debate
n 
Response to therapies relatively poor
n 
Unclear outcome in adulthood
+ Bipolar disorder
in children and adolescents
Duffy CJP 2010
+ Bipolar disorder
in children and adolescents
Kraepelin:
0.4% (on 900 patients) onset before 10 years of age
Antony & Scott (1960)
Stringent criteria: extremely rare
Loranger & Levine (1978) 0.5 % onset before age 10, 7,5% 10-14 y (n=200)
Goodwin & Jamison (1990) 0.3 % onset before age 10, 3% 10-14 aa (n=900)
Potter (1983) Poznanski (1984) ADHD & Bipolar D. comorbidity
ADHD & Bipolar D. comorbidity ( a separate entity?)
Carlson 1983, 1984, 1988,
Biederman 1995, 1996;
Geller 1995, 1996;
Wozniack 1995, 1996
+ Disturbo bipolare in età evolutiva
A. Disturbo bipolare I
B. Disturbo bipolare II
C. Disturbo ciclotimico
D. Disturbo depressivo maggiore
E. Disturbo distimico
+ Disturbo bipolare DSM IV -TR
A. Almeno un episodio maniacale o misto
B. Significativa compromissione del funzionamento globale
C. Escludere schizofrenia, d. schizofreniforme o d. delirante
D. Specificare:
a. decorso longitudinale (recupero funzionale intercritico)
b. pattern stagionale ( ep. Depressivo)
c. ciclicita’ rapida
e. Severita’/ sint. Psicotici
f. catatonia
h. Esordio post partum
+ Episodio Maniacale DSM IV -TR
A. Un periodo di umore persistentemente elevato, espansivo e/o irritabile,
della durata di almeno una settimana o tale da richiedere
l’ospedalizzazione
B. Tre (4 se umore irritabile) o più dei seguenti sintomi:
1. Aumentata autostima o grandiosita’
2. Diminuito bisogno di sonno
3. Logorrea
4. Fuga delle idee
5. Eccessiva Distraibilità
6. Aumentata attività finalizzata (sociale o sessuale)/ agitazione psicomotoria
7. Eccessivo coinvolgimento in attività piacevoli ma potenzialmente pericolose
C. . Escludere l’episodio misto, l’uso di sostanze o una condizione medica generale.
D. Compromissione significativa del funzionamento sociale, lavorativo o scolastico
E. Ospedalizzazione, sintomi psicotici
+ Episodio Ipomaniacale DSM IV -TR
A. Sintomi presenti per almeno 4 giorni
B. Minore intensità e durata
C. Evidente modifiche del funzionamento funzionamento globale
con comportamenti non caratteristici della persona quando
eutimica
D. Il disturbo dell’umore e la compromissione del comportamento
sono riconoscibili dagli altri
E. Compromissione del funzionamento globale non tale da imporre
ospedalizzazione. Presenza di sintomi psicotici.
F. Non dovuto ad effetti di sostanze o altre condizioni mediche
+ Disturbo Ciclotimico DSM IV -TR
A. . In almeno due anni presenza di numerosi episodi ipomaniacali e
sintomi depressivi di intensità insufficiente a porre diagnosi di
episodio depressivo maggiore
B. Durante tale periodo (2 anni), assenza di periodi intercritici di
benessere superiori ai 2mesi
C. Assenza di franchi episodi maniacali, depressivi o misti
D. Escludere schizofrenia, d. schizofreniforme o d. delirante
E. Escludere uso di sostanze o altra causa internistica.
F. Significativo stress o compromissione del funzionamento globale
+
CBCL clinical scales discriminate prepuberal
children with structured interview derived
diagnosis of mania from those with ADHD
Biederman JAACAP 1995
+
Bipolar disorder in children and adolescents
in Germany: national trends in the rates
of inpatients, 2000–2007
Holtman Bipolar Disorder 2010
+
Complex and rapid-cycling in bipolar children
and adolescents: a preliminary study
26 patients (age 7-16 y) K-SADS-PE (DSM-III-R) diagnosis of bipolar
disorder: numeber nad duartion of episodes
Age at onset: 8,5+4,4 annni
Frequent comorbidity: separation axiety , DOC, Conduct D.
80% of cases: “continous rapid cycling”
(hundreds of episods lasting less than a day).
Psychotic symptoms (hallucinations 23%, delusion 34%), suicidality,
hyperactivity, “mixed mania” extremely frequent.
Geller et al. J.Aff.Disordes 1995
Attack Types at Different Ages
100
90
80
70
60
50
40
30
20
10
0
Years
Mixed Attack
Melancholic Attack
Percentage
Mixed
Manic Attack
15
20
25
30
35
40
45
Kraepelin. Manic Depressive Insanity and Paranoia.
Edinburgh: E&S Livingstone; 1921:169.
50
55
60
65
Bipolar?
lar?
Neuropsicologia
+
del Disturbo bipolare in età evolutiva
u 
Deficit di memoria verbale e di lavoro e attenzione sostenuta
u 
u 
u 
Doyle et al. 2005, McClure etal. 2005; Pavuluri et al. 2006,
ma anche DelBello et al. 2004, Robertson et al. 2003
Deficit controllo emotivo
u  Difficoltà
di adattamento, del comportamento per modificazioni delle
contingenze delle ricompense (deficit in flessibilità= Anedonia,
ipertimia)
Dickens et al 2004; McClure et al. 2005
u  Difficoltà
u  Inabilità
nel definire le emozioni nella facce McClure et al. 2005
a focalizzare l’attenzione con forti emozioni Rich et a. 2005
+ NeuroAnatomia
del Disturbo bipolare in età evolutiva
u 
Diminuito volume dell’amigdala
u 
Blumberg et al. 2003, Chang et al. 2005; Del Bello et al. 2004 Dickinson et al.
2005,
u 
Diminuito volume dell’Ippocampo Bearden et al. 2004
u 
Alterazioni corteccia prefrontale dorso laterale e
orbitofrontale
u  OF-PFC:più
al 2007
piccola nei maschi più grande nelle femmine Najt et
Neuro
Imaging
funzionale
+
nel Disturbo bipolare in età evolutiva
u 
Stroop task: aumentata attività stritale Blumberg et al. 2003
u 
Motor inhibition task: Ridotto error signal striatale Liebenluft et al.
2007
u 
Percezione di facce neutre come ostili: aumentata attività di
amigdala e striato McCLure te la 2007 , Rich et al. 2006
u 
Diminuito NAA in DL-PFC: aumento con litio e con remissione
u 
Aumento di mi- Inositolo (mI) in ACC: si riduce col litio
Chang et al. 2003, Manji et al. 2000, Del Bello et al. 2006 [OLA], Davanzo et al. 2003
+
Penn Emotion Differentiation Test
+
Penn Emotional Acuity Test PEAT
+
PBD vs HC: response to Angry Face
Pavuluri et al. Biol Psychiatry
2006
+
PBD vs HC: response to Angry Face
Amigdala
hyperactivation
Pavuluri et al. Biol Psychiatry 2006
+
+
+ Amigdala response to negative words
Pavulutri et al. Psych.Res. Neuroimage 2007
+
Cinque circuiti funzionali in PBD
Pavulutri & Sweeney JAACAP
+ Criteria for establishing reliable and valid
phenotypes of Juvenile Mania
1. Consistent clinical description
2. Consistent findings in physiologic / neuropsychological studies
3. Clear delimitation from other disorders
4. Consistent clinical outcomes found in follow-up studies
5. Increased prevalence in relatives found in family and genetic
studies
Leibenluft AJP 2003
+ Defining Clinical Phenotypes
of Juvenile Mania
Phenotypes
ü  Narrow
(Hypo) Mania: Full duration episodes, Hallmark symptoms
ü  Intermediate
- (Hypo) Mania NOS: Short episodes, Hallmark symptoms
-Irritable (Hypo) Mania:
Full duration episodes,
NO Hallmark symptoms
ü  Broad
Severe Mood and Behavioural Dysregulation
Leibenluft AJP 2003
Defining Clinical Phenotypes
+
of Juvenile Mania
Leibenluft AJP 2003
Inclusion Criteria for the Broad Phenotype
Age 7-17 , onset before age 12
1. Abnormal mood (anger, sadness) present at least half of the day, almost
every day, noticeable by other (severity)
2. Compared with peers : markedly increased reactivity to negative
emotionally stimuli, verbally or behavioral manifested (intensity)
3. Symptom currently present, for at least 12 months with no symptom free
period longer than 2 months (duration)
4. Severe symptoms in at least one setting AND at least mild symptoms in
another setting (pervasiveness)
Other definition: Severe Mood Dysregulation
Possible conceptualization: Severe ADHD + ODD
+
Four-Year Prospective Outcome
and Natural History of Mania
in Children With a Prepubertal
and Early Adolescent
Bipolar Disorder Phenotype
Geller et al. Arch Gen Psych. 2006
+
Four-Year Prospective Outcome
and Natural History of Mania
in Children With a Prepubertal
and Early Adolescent
Bipolar Disorder Phenotype
Geller et al. Arch Gen Psych. 2006
+
Four-Year Prospective Outcome
and Natural History of Mania
in Children With a Prepubertal
and Early Adolescent
Bipolar Disorder Phenotype
Geller et al. Arch Gen Psych. 2006
+
Four-Year Prospective Outcome and Natural History of Mania
in Children With a Prepubertal and Early Adolescent
Bipolar Disorder Phenotype
Geller et al. Arch Gen Psych. 2006
Recovery and relapse
100
Subjects who Recovered
87,2
Subjects who Relapsed after Recovery
80
77,9
65,1
60
55,8
64
55,4
53,7
% Subjects
39,6
36
40
29
20
14
16,7
0
6
12
18
24
Follow-up months
36
48
+ Disturbo Bipolare in età evolutiva
Strategie terapeutiche
ü Terapia farmacologica di episodi acuti, prevenzione delle
ricadute, stabilizzazione intercritica
ü Terapia profilattica per almeno 18 mesi
ü Rischio di farmacoresistenza per intempestiva sospensione
ü Interventi psicosociali di supporto
+
Sali di Litio in eta’ evolutiva
Vantaggi
 
 
Efficacia ben
documentata
Ampia letteratura
anche in eta’ evolutiva
Svantaggi
  Lento
inizio di attivita’ (1-6
settimane)
  Necessari
periodici.
  Possibile
es.ematochimici
tossicita’ renale e tiroidea
  Tremore, Poliuria
e polidipsia,
  Nausea, Aumento
di peso, Acne.
Valproato in eta’ evolutiva
Svantaggi
Vantaggi
 
Efficacia antimaniacale
documentata
 
Letteratura su eta’ evolutiva
 
Possibilita’ di carico orale acuto
 
Efficacia a lungo termine (profilassi) non
documentata
 
Necessari es. ematochimici periodici.
 
Possibile trombocitopenia e/o alterazioni
piastriniche
 
Possibile tossicità epatica
 
Associazione con ovaio policistico
 
Nausea, Vomito, Aumento di peso,
Sedazione,Tremore
Nuovi antipsicotici: classificazione
farmacodinamica
M1
SDA
α1
Risperidone
Ziprasidone
H1
α1
MARTA*
Clozapina
5-HT2C Olanzapina
Quetiapina
5-HT
7
D2
α2
D2
D3
*Multi-Acting Receptor Targeted Antipsychotics
ANTAGONISTI
SELETTIVI D2D3
AGONISTI
DOPAMINERGI
CI PARZIALI
Amisulpride
Aripiprazolo
D3
D2
D2
D3
Prospective Outcome and Natural History of Mania
+ Four-Year
in Children With a Prepubertal and Early Adolescent
Bipolar Disorder Phenotype
Geller et al. Arch Gen Psych. 2006
+ Child Bipolar I Disorder
Prospective Continuity With Adult Bipolar I Disorder;
Characteristics of Second and Third Episodes; Predictors of 8Year Outcome
Geller et al. Arch Gen Psych. 2008
+ Child Bipolar I Disorder
Clinical Course of Children and Adolescents
With Bipolar Spectrum Disorders Birmaher et al. AGP 2006
Clinical Course of Children and Adolescents
With Bipolar Spectrum Disorders Birmaher et al. AGP 2006
The British Child and Adolescent mental Health Survey 1999:
The prevalence of DSM-IV disorders. JAACAP 2003
10405 Parent interviews
4115 Adolescent (11-15y) interviews
8382 Teacher interviews
D.Ansia
5-7
8-10
11-12
13-15
Male
Female
Total
3,19
3,05
3,95
5,04
3,50
4,04
3,77
0,14
0,21
0,63
0,26
0,24
0,25
0,16
0,57
0,74
0,18
0,57
0,73
0,65
0,14
0,34
0,71
2,53
0,87
0,97
0,92
0,14
0,27
0,44
1,87
0,65
0,72
0,68
5,00
5,88
5,85
7,04
8,50
3,31
5,90
2,49
2,57
2,10
3,62
0,85
2,23
0,78
1,25
3,31
2,13
0,81
1,47
OCD 0,03
Ansia Gen.
Depressione
Depr.Magg.
D. Dirompenti
ADHD 1,90
D.Condotta 0,59
PDD
0,40
,031
0,09
0,24
0,47
0,09
0,29
Other/ NAS
1,16
1,58
2,17
3,61
2,40
1,80
2,09
Early onset Bipolar Disorder +
A Sardinian case series Subjects 71 inpa'ents, aged 6 to 18 years, mee0ng DSM-­‐IV diagnos0c criteria for BP-­‐I (n=45), BP-­‐II (n=10) and BP-­‐NOS (n=16). Subjects were admi?ed to the Neuropsychiatric Unit of the University Hospital of Cagliari, between 1996 and 2007, due to a severe acute affec0ve episode (CGAS≤45) The pa0ents were followed up for 24 months and response to drug and the longitudinal course of the disorder was assessed at baseline, 6, 12 and 24 months by the Children Global Assessment Scale (C-­‐GAS) +
Assessment
• 
Schedule for affec0ve disorders and schizophrenia for school-­‐age children Present and Life0me version (Kiddie-­‐SADS-­‐PL Kaufman 1996) At admission and retrospec0ve; pa0ents & parent • 
History of previous psychiatric and medical illnesses and parental psychopathology • 
Young Mania Ra0ng Scale (YMRS)
• 
assessment (WISC-­‐R or WAIS-­‐R); IQ • 
Children Global Assessment Scale (C-­‐GAS); • 
Clinical Global Impression Severity (CGI-­‐S); • 
Medical evalua0on: physical and neurological examina0on, rou0ne blood screening, thyroid func0on tests, EKG, EEG, vital signs including blood pressure, pulse, height and weight. +
METHODS Treatment n 
Pa0ents received a psychopharmacological treatment: §  Monotherapy with mood stabilizers (lithium or VPA) or §  Monotherapy with an'psycho'cs (SGA or FGA) or §  Combina'on therapy if there was par0al or no response. Some of the pa0ents needed addi0onal treatments related to their comorbidi0es (psychos0mulants, SSRIs, benzodiazepines). n 
Ader discharge, pharmacological treatment was strictly monitored at each visit (weekly or monthly). n 
All the pa0ents and their families received a structured psychoeduca'onal support +
METHODS STATISTICAL ANALYSIS Ø  Categorical comparisons were based on con0ngency tables (χ2); Ø  Con0nuous variables were compared by one-­‐way ANOVA. Ø Repeated measures ANOVA was performed for C-­‐GAS scores at baseline, 6, 12 and 24 month follow up. Sta0s0cal significance required two-­‐tailed p≤0.05. +
Demographic and clinical characteris'cs of the sample BD I
(n=45)
BD II
(n=10)
BD NOS
(n=16)
p
29 (64.4)
6 (60)
13 (81.3)
n.s.
Prepuberal onset n (%)
4 (8.9)
3 (30)
12 (75)
<0.001đ
1st psych examination (mean ± DS)
14±3.6
12.5±4.7
7.6±3.9
<0.001*
Age at onset (mean ± DS)
15.2±2
13.4±2.9
11.2±3.3
<0.001*
Age at 1st medication (mean ± DS)
15±2.6
14±2.5
11.1±3.4
0.001*
Age at admission (mean ± DS)
15.2±2.4
14±2.2
12±3.3
0.004*
IQ >80 n (%)
IQ 70-55 n (%)
33 (73.3)
8 (17.8)
8 (80)
1 (10)
8 (50)
4 (25)
n.s.
4 (8.9)
1 (10)
4 (25)
11 (24.4)
4 (8.9)
4 (40)
0
3 (18.8)
0
n.s.
n.s.
ADHD
5 (11.1)
4 (40)
9 (56.3)
0.001đ
ODD
5 (11.1)
3 (30)
6 (37.5)
0.03đ
3 (6.7)
1 (10)
1 (6.3)
n.s.
10 (22.2)
2 (20)
1 (6.3)
n.s.
Males n (%)
IQ <55 n (%)
Comorbidity n (%)
Anxiety
OCD
CD
Substance use
* Kruskal Wallis test ₫ χ2 test +
FAMILY HISTORY BD I
(n=45)
BD II
(n=10)
BD NOS
(n=16)
P (X2)
Positive family history
34 (75.5)
8 (80)
13 (81.3)
n.s.
Mood Disorder
26 (57.7)
4 (40)
6 (37.5)
n.s.
7 (15.6)
0
2 (12.5)
n.s.
Anxiety
2 (4.4)
2 (20)
2 (12.5)
n.s.
ADHD
2 (4.4)
2 (20)
3 (18.8)
n.s.
CD
1 (2.2)
1 (10)
2 (12.5)
n.s.
7 (15.6)
1 (20)
4 (25)
n.s.
2 (4.4)
0
2 (12.5)
n.s.
Family History n (%)
Psychosis
Substance abuse
Suicide
+
Polarity and Severity of Index Episode BD I
(n=45)
BD II
(n=10)
BD NOS
(n=16)
P (X2)
26 (57.8)
10 (22.2)
4 (40)
1 (10)
11 (68.8)
3 (18.8)
9 (20)
5 (50)
2 (12.5)
Suicidal ideation
16 (35.5)
7 (70)
7 (43.5)
0.045
Suicide attempts
4 (8.9)
2 (20)
2 (12.5)
n.s.
44 (97.8)
7 (70)
16 (100)
0.001
CGI-S =4
6 (13.3)
2 (20)
8 (50.0)
CGI–S= 5
CGI–S= 6
30 (66.7)
9 (20)
7 (70)
1 (10)
6 (37.5)
2 (12.5)
Polarity of index episode n(%)
Mixed
Manic/Hypomanic
Depressed
n.s.
Severity of index episode n(%)
Absence of Insight
0.05
K-­‐SADS AT INDEX EPISODE BD I
(n=45)
BD II
(n=10)
BD NOS
(n=16)
P (X2)
14 (31.1)
2 (20)
2 (11.5)
Depressed mood (severe)
18 (40)
8 (80)
11 (68.8)
Irritable mood (moderate)
Irritable mood (severe)
10 (22.2)
29 (64.4)
3 (30)
7 (70)
1 (6.3)
15 (93.8)
n.s.
Anhedonia (moderate)
Anhedonia (severe)
11 (24.4)
13 (28.9)
3 (30)
6 (60)
8 (50)
5 (31.3)
0.05
Thoughts of death (moderate)
Thoughts of death (severe)
8 (17.8)
4 (8.9)
2 (20)
6 (60)
3 (18.8)
3 (18.8)
0.004
Suicidal ideas (moderate)
Suicidal ideas (severe)
6 (13.3)
6 (13.3)
2 (20)
5 (50)
4 (25)
3 (18.8)
0.060
Elated mood (moderate)
Elated mood (severe)
9 (20)
29 (64.4)
7 (70)
1 (10)
8 (50)
4 (25)
0.004
Decreased sleep (moderate)
Decreased sleep (severe)
12 (26.7)
27 (60)
2 (20)
2 (20)
5 (31.3)
3 (18.8)
0.003
Increased energy (moderate)
Increased energy (severe)
13 (28.9)
18 (40)
3 (30)
0
3 (18.8)
1 (6.3)
0.005
Flight of ideas (moderate)
Flight of ideas (severe)
14 (31.1)
20 (44.4)
2 (20)
0
1 (6.3)
2 (12.5)
<0.001
Hallucination (moderate)
Hallucination (severe)
11 (24.4)
17 (37.8)
0
1 (10)
1 (6.3)
2 (12.5)
0.005
Delusion (moderate)
Delusion (severe)
5 (11.1)
30 (66.7)
2(20)
0
1 (6.3)
2 (12.5)
<0.001
Symptoms at onset n (%)
Depressed mood (moderate)
0.070
+
PHARMACOLOGICAL TREATMENT AT INTAKE Medication n (%)
BD I
(n=45)
BD II
(n=10)
BD NOS
(n=16)
P (X2)
Mood Stabilizer
2 (4.4)
6 (60)
8 (50)
<0.001
Mood Stabilizer + AP
23 (51.1)
2 (20)
3 (18.8)
0.030
AP
19 (42.2)
1 (10)
5 (31.3)
n.s.
1 (2.2)
1 (10)
0
n.s.
Litihium
VPA
8 (17.8)
20 (44.4)
2 (20.0)
7 (70)
1 (6.3)
11 (68.7)
n.s.
n.s.
SG Antipsychotics
26 (57.8)
3 (30)
8 (50)
n.s.
FG Antipsychotics
19 (42.2)
0
1 (6.3)
0.002
MPH
2 (4.4)
1 (10)
5 (31.3)
0.014
SSRI
2 (4.4)
4 (40)
1 (6.3)
0.003
15 (34.1)
4 (40)
1 (6.3)
n.s.
None or other drugs
Specific Drugs n (%)
Benzodiazepine
+
PHARMACOLOGICAL TREATMENT AT 6 MONTHS Medication n (%)
BD I
(n=45)
BD II
(n=10)
BD NOS
(n=16)
P (X2)
Mood Stabilizer
5 (11.1)
4 (40)
6 (37.5)
0.05
Mood Stabilizer + AP
25 (55.6)
4 (40)
6 (37.5)
n.s.
AP
10 (22.2)
0
2 (12.5)
n.s.
5 (11.1)
2 (20)
2 (12.5)
n.s.
Litihium
14 (31.1)
2 (20.0)
2 (12.5)
n.s.
VPA
19 (42.2)
7 (70)
11 (68.7)
n.s.
SG Antipsychotics
30 (66.7)
3 (30)
6 (37.5)
0.031
FG Antipsychotics
7 (15.6)
1 (10)
2 (12.5)
n.s.
MPH
2 (4.4)
2 (20)
7 (43.8)
0.001
SSRI
5 (11.4)
2 (20)
2 (12.5)
n.s.
2 (4.4)
1 (10)
0
n.s.
None or other drugs
Specific Drugs n (%)
Benzodiazepine
+
PHARMACOLOGICAL TREATMENT AT 24 MONTHS Medication n (%)
BD I
(n=45)
BD II
(n=10)
BD NOS
(n=16)
P (X2)
Mood Stabilizer
8 (17.8)
7 (70)
6 (37.5)
0.003
24 (53.3)
3 (30)
3 (18.8)
0.039
AP
7 (15.6)
0
3 (18.8)
n.s.
None or other drugs
6 (13.3)
0
4 (20)
n.s.
Lithium
16 (35.6)
5 (50)
3 (18.8)
n.s.
VPA
23 (51.1)
7 (70)
7 (43.8)
n.s.
SG Antipsychotics
26 (57.7)
2 (20)
4 (25)
0.014
FG Antipsychotics
4 (8.8)
2 (20)
2 (12.5)
n.s.
MPH
1 (2.2)
2 (20)
4 (20)
0.018
SSRI
3 (6.7)
2 (20)
1 (6.3)
n.s.
0
0
2 (12.5)
0.03
Mood Stabilizer + AP
Specific Drugs n (%)
Benzodiazepine
C-­‐GAS +
75 BD I 70 BD II 65 BD NOS 60 CGAS 55 50 **
45 40 35 30 *
25 T0 T 6 T 12 T 24 N
baseline
6 month
12 month
24 month
BD I
45
32±6.3*b
48.3±9.00
51.7±12.4
56.7±14.1
BD II
10
39±5.2e
50±9.7
56±11.7
56±16.8
BD NOS
16
36.7±7.2f
45.2±8.8
46.2±9.4
46.1±7.8**
* p=0.002 (compared to BD-II and BD-NOS at baseline); * * p= 0.029 (compared to BD-I and II at 24 month)
b p=<0.001; e p=0.026; f p= 0.002 (each group compared to 6 month)
+
IQ 70
65
60
CGAS
55
IQ<55
50
IQ 70-55
IQ>80
45
40
35
30
T0
T6
T12
T24
N
baseline
6 month
12 month
24 month
9
30.5±5.8
46.67±10.6
42.7±15.4
45.5±11.5
QI 55-70
13
33.08±8.7
44.8±8.8
50.7±10.9
51.77±13.9
QI>70
49
34.9±6.4
48.8±8.8
52.6±11.04
56.4±13.8
QI<55
p=0.006 (between subjects ANOVA)
+
LIMITATIONS ü  The retrospec0ve design of the study ü 
The rela0vely small sample size ü 
The inclusion of exclusevely severely ill pa0ents (inpa0ents and C-­‐GAS ≤ 45) ü 
The short follow up 0me (24 month) ü 
Few variables selected in the analysis of predic0ve factors + Early onset bipolar “spectrum”
a tentative “clinical” nosology
BD-I
BD-II
BD-NOS
SMD
ODD
ADHD
+ Early onset bipolar “spectrum”
a tentative “clinical” nosology
BD-I
BD-II
BD-NOS
SMD
ODD
ADHD
Stingaris JAACAP 2010
Temper Dysregulation Disorder
with Dysphoria (DSM-V)
+ The Treatment of Early-Age Mania Study (TEAM)
Multisite, 8 week, RCT of Li+, risperidone and VPA in children (6 -15)
with DSM-IV BD-I (mixed or manic phase).
Subjects (N=379, age 10.2±2.7 years, 46.2% female) has persistence of
n  manic symptoms (4.9±2.6 years),
n  prominent elation or grandiosity (100%),
n  high rates of psychosis (79.9%),
n  mixed mania (97.9%)
n  rapid cycling (98.9%).
The primary outcome
Clinical Global Impression-Improvement Scale for mania (CGI-I mania)
Adverse effects were assessed by Modified Side Effects Form for
Children and Adolescents.
+ The Treatment of Early-Age Mania Study (TEAM)
290 medication-naïve participants,
210 (72.4%) completed eight weeks of treatment
Titrated blood levels were Li+ 1.09±0.34 mEq/
VPA 113.6±23.0 mcg/mL
Risperidone titrated to 2.57±1.21 mg/d.
Response rates on CGI-I-Mania were significantly higher for
risperidone vs. lithium (65.6% vs. 34.4%, p<0.001)
risperidone vs. valproate (65.6% vs. 23.1%, p<0.001).
Subjects on RISP had significantly higher response rates than on LI+ or VPA
CGI-I mania
46.2% vs. 25.8%, X2=7.5, df=1, p=0.006;
46.2% vs. 16.3%, X2=15.2, df=1, p<0.001
Absence of mania diagnosis
60.2% vs. 39.8%, X2=5.7, df=1, p=0.017;
60.2% vs. 25.0%, X2=18.3, df=1, p<0.001
+ The Treatment of Early-Age Mania Study (TEAM)
290 medication-naïve participants,
210 (72.4%) completed 8 weeks treatment.
Discontinuation rates were
19.4% for risperidone,
34.4% for lithium (p=0.022 vs RISP)
28.8% for valproate,
Mean weight gain was higher with
risperidone (3.31±1.75kg) than
lithium (1.42±1.62kg, p<0.001) or
valproate (1.67±1.92kg, p<0.001).
+The Treatment of Early-Age Mania Study (TEAM)
Prolactin levels increased 37.6 mcg/mL with risperidone,
which differed (p<0.001) from the minimal changes with lithium and
valproate
There was a significant difference between
- increased low-density lipoprotein (LDL) on risperidone and decreased
LDL on valproate (2.2±16.9 vs. -6.7±20.8 mg/dL, F1,210=8.0, p=0.005)
- decreased high-density lipoprotein (HDL) on risperidone and
increased HDL on valproate (-2.3±18.4 vs. 4.1±8.6 mg/dL, F1,213=7.3,
p=0.008)
Serious adverse events were reported in five participants; none were
deemed to be related to study medication.
)