Download Plastic Surgery for the General Surgeon

Bipolar Disorder in Children
and Adolescents
Robert A. Kowatch, MD, PhD
Professor of Psychiatry
The Ohio State University’s Wexner Medical Center
Nationwide Children’s Hospital
Center for Innovation in Pediatric Practice
DSM-IV Bipolar Disorders
• Bipolar I Disorder
• “Manic Depressive Illness”
• Bipolar II Disorder
• Cyclothymia
• Bipolar Not Otherwise Specified
• BP “NOS”
Lifetime Prevalence of Bipolar
Disorder in the USA
• Adults (NCS Replication Study, Merikangas et al.
2007)
• Bipolar I Disorder: 1.0%
• Bipolar II Disorder: 1.1%
• Bipolar Subthreshold: 2.4%
• Adolescents
• Bipolar Disorder: 1.0-1.4%
• Children
• ???
Goodwin and Jamison, Manic Depressive Illness, March 22, 2007 | ISBN-10: 0195135792 | ISBN-13: 9780195135794 | Edition: 2
Topics
• Differential
diagnosis of
mood swings
in children and
adolescents
• Pharmacothera
py of pediatric
bipolar
disorder
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Differential Diagnosis
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Other disorders that frequently
cause mood swings
•
•
•
•
ADHD
ODD
Anxiety Disorders
Fetal Alcohol Spectrum Disorder
• (ARND)
Attention-Deficit/Hyperactivity
Disorder (ADHD)
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Attention Deficit Hyperactivity
Disorder DSMIV Criteria
• A persistent pattern of inattention and/or hyperactivityimpulsivity that is more frequent and severe than is
typically observed in individuals at a comparable level of
development
• Some impairment from the symptoms must be present in
at least 2 settings (e.g., at home and at school)
• There must be clear evidence of interference with
developmentally appropriate social, academic, or
occupational functioning
• Present before age 7 years
• 6 symptoms for at least 6 months
Prepubertal & Early Adolescent
Bipolarity Differentiate From ADHD
by Manic Symptoms
 Subjects
 60 Bipolar Subjects with ADHD
 Mean age of 11 + 2.7 yr.
 60 ADHD Subjects with no mood
disorder
 Mean age of 9.6 + 2 yr.
 Method
 CGAS < 60
 WASH-U-KSADS, 16 Mania Items
 Mothers
 Children & Adolescents
Geller & Williams 1998
Oppositional Defiant Disorder
(ODD)
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DSMIV Criteria for
Oppositional Defiant Disorder
•
A. A pattern of negativistic, hostile, and defiant behavior lasting at
least 6 months, during which four (or more) of the following are
present:
•
Often loses temper
•
Often argues with adults
•
Often actively defies or refuses to comply with adults' requests
or rules
•
Often deliberately annoys people
•
Often blames others for his or her mistakes or misbehavior
•
Is often touchy or easily annoyed by others
•
Is often angry and resentful
•
Is often spiteful or vindictive
•
B. The disturbance in behavior causes clinically significant
impairment
•
C. The behaviors do not occur exclusively during the course of a
Psychotic or Mood Disorder
•
D. Criteria are not met for Conduct Disorder
ODD vs. BPD
Symptoms
ODD
BPD
Often loses temper
+
+
Often argues with adults
+
+/-
Often actively defies or refuses to comply with adults'
requests or rules
+
+/-
Often deliberately annoys people
+
+
ODD vs. BPD
Symptoms
ODD
BPD
Often loses temper
+
+
Often argues with adults
+
+/-
Often actively defies or refuses to comply with adults'
requests or rules
+
+/-
Often deliberately annoys people
+
+
Euphoria/Irritability
-
Inflated Self Esteem/grandiosity
-
+
+
Decreased Need for Sleep
-
More Talkative/Pressured Speech
-
Flight of Ideas/Racing Thoughts
-
Distractibility
-
Increased Goal Activity/Agitation
-
Excessive Involvement in Pleasurable Activities
-
+
+
+
+
+
+
Anxiety Disorders
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Lifetime prevalence of mental
disorders in U.S. adolescents
35
32
30
Lifetime Prevalence
25
With Severe
Impairment
20
%
20
15
14
11
10
10
11
8
5
2.7
0
Mood
Anxiety
Behavior
Substance Use
Eating Dis
Merikangas et al., J Am Acad Child Adolesc Psychiatry. 2010 Oct
Anxiety Disorders
 Generalized Anxiety Disorder (GAD)
 Worry a lot
 Headaches/Stomach Aches
 Anxiety often causes mood swings
 OCD
 Symptoms > 1 Hour/Day
 Obsessions
 Compulsions
 “Just Right” Phenomena
 Frequent mood swings if things don’t go just right
Fetal Alcohol Disorders
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Fetal Alcohol Syndrome (FAS)
 Maternal alcohol use during pregnancy
 Growth deficiencies
 stunted prenatal and/or postnatal growth
 Permanent brain damage resulting in neurological
abnormalities, delay in development, intellectual
impairment and learning/behavior disabilities
 Abnormal facial features including short eye
opening, short nose, flat midface, thin upper lip and
small chin
Fetal Alcohol Syndrome Facies
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Fetal Alcohol Syndrome (FAS)
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Alcohol-Related Neurodevelopmental
Disorder (ARND)
•
•
•
•
•
•
•
•
•
Full Dysmorphia Absent
Poor impulse control
Problems in social perception
Deficits in higher level receptive and expressive
language
Problems in memory, attention, or judgment
learning
Difficulties, deficits in school performance
Poor capacity for abstraction or metacognition
Specific deficits in mathematical skills
Mood Dysregulation
Disruptive Mood
Dysregulation Disorder
(DMDD)
Slides Courtesy of
David Axelson, M.D.
Associate Professor of Psychiatry
Western Psychiatric Institute & Clinic - UPMC
DSM-5 Proposal: Disruptive Mood
Dysregulation Disorder
•
•
•
•
•
A. The disorder is characterized by severe recurrent temper
outbursts in response to common stressors.
B. The temper outbursts are manifest verbally and/or
behaviorally, such as in the form of verbal rages, or physical
aggression towards people or property.
C. The reaction is grossly out of proportion in intensity or
duration to the situation or provocation.
• The responses are inconsistent with developmental level.
Frequency
• The temper outbursts occur, on average, three or more
times per week.
Mood between temper outbursts:
• Nearly every day, the mood between temper outbursts is
persistently negative (irritable, angry, and/or sad).
• The negative mood is observable by others (e.g., parents,
teachers, peers).
DMDD vs. Severe Mood Dysregulation
(SMD)
• TDD is similar to SMD except the symptoms
of hyperarousal have been removed
• SMD Hyperarousal Symptoms (need at least
3)
• Insomnia
• Agitation
• Distractibility
• Racing thoughts
• Flight of ideas
• Pressured speech
• Intrusiveness
Temper Dysregulation Disorder
with Dysphoria Criteria
• Duration: Criteria A-C have been present for at least 12
months. Throughout that time, the person has never
been without the symptoms of Criteria A-C for more than
3 months at a time.
• The temper outbursts and/or negative mood are present
in at least two settings (at home, at school, or with peers)
and must be severe in at least in one setting.
• Chronological age is at least 6 years (or equivalent
developmental level).
• The onset is before age 10 years.
Temper Dysregulation Disorder with
Dysphoria (cont.)
• In the past year, there has never been a distinct period
lasting more than one day during which abnormally
elevated or expansive mood was present most of the
day for most days, and the abnormally elevated or
expansive mood was accompanied by the onset, or
worsening, of three of the “B” criteria of mania (i.e.,
grandiosity or inflated self esteem, decreased need for
sleep, pressured speech, flight of ideas, distractibility,
increase in goal directed activity, or excessive
involvement in activities with a high potential for painful
consequences; see pp. XX). Abnormally elevated mood
should be differentiated from developmentally
appropriate mood elevation, such as occurs in the
context of a highly positive event or its anticipation.
Disruptive Mood Dysregulation
Disorder
•
The behaviors do not occur exclusively
during the course of a Psychotic or Mood
Disorder (e.g., Major Depressive Disorder,
Dysthymic Disorder, Bipolar Disorder) and
are not better accounted for by another
mental disorder (e.g., Pervasive
Developmental Disorder, post-traumatic
stress disorder, separation anxiety disorder).
(Note: This diagnosis can co-exist with
Oppositional Defiant Disorder, ADHD,
Conduct Disorder, and Substance Use
Disorders.)
• The symptoms are not due to the direct
physiological effects of a drug of abuse, or to
a general medical or neurological condition.
DSM-V rationale for DMDD
• Marked upsurge in the diagnosis of bipolar disorder
in youth
• Coincided with debate as to whether mania in
children presented with severe, non-episodic
irritability
• Presented support from post-hoc analyses of
longitudinal epidemiological studies that chronic
irritability does not progress to bipolar disorder in
young adulthood
• Evidence from Severe Mood Dysregulation (SMD)
studies in regard to differences between SMD vs.
Narrow Phenotype BP youth in short-term course,
family history and neural circuitry
DMDD Rationale (con’t)
• Noted scientific support is limited but clinical need was
strong for a separate diagnosis (instead of a course
specifier for ODD)
• “Based purely on scientific evidence, inclusion of a
specifier might be most easily justified. However, when
both clinical need and scientific evidence are considered
together, a different conclusion emerges.”
Issues Pertinent to a Developmental Approach to Bipolar Disorder in DSM-5.
accessed from www.dsm5.org. American Psychiatric Association, 2010
Problems with TDD
• “…it is clear that, from a pathophysiological perspective,
TDD is unlikely to be categorically distinct from ODD,
which is itself a heterogeneous category with disparate
longitudinal outcomes.”1
• “It can certainly be argued that it is premature to suggest
the addition of the TDD diagnosis to DSM-V, since the
work has been done predominately by one research
group in a select research setting”2
1Issues
Pertinent to a Developmental Approach to Bipolar Disorder in DSM-5. accessed
from www.dsm5.org. American Psychiatric Association, 2010
2DSM-5
Childhood and Adolescent Disorders Work Group. Justification for Temper
Dysregulation Disorder with Dysphoria. accessed from www.dsm5.org. American
Psychiatric Association, 2010
Problems with DMDD
• Abnormal mood, but no accompanying symptoms
(temper outbursts are a behavioral manifestation of
irritable mood)
• Research support from studies of SMD, not TDD
• Likely to be a very heterogeneous population
• Almost all (85%) have ODD and ADHD
• Difficult to determine “not exclusively during mood
disorder” & “not better accounted for by ASD, PTSD…”
in clinical settings
• May be overly broadly applied
• May stimulate drug companies to get FDA indication for
TDD
Mood Swings Quick Guide
Higher Level of Suspicion
 Family history of mood disorders
 Episodes of aggressive behavior
 in the context of other manic symptoms





Early age of onset for depression
Mood disorder with psychotic features
Recurrent depressive episodes resistive to treatment
Episodic presentation of ADHD
Mood destabilization secondary to stimulant or
antidepressant
When you hear hoof beats (mood
swings)…
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When you hear hoof beats (mood
swings)…
Pharmacotherapy of Children
and Adolescents with
Bipolar Disorder
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How many, large (n>100), placebocontrolled, double-blinded trials are there
for mania in children and adolescents?
1. 2
2. 4
3. 9
4. 12
Large Controlled Trials in
Pediatric Mania
Trial
n
Oxcarbazepine (Trileptal)
116
PBC: Lithium vs DVP
153
Sodium Divalproex (Depakote ER)
150
Risperidone (Risperdal)
169
Olanzapine (Zyprexa)
161
Quetiapine (Seroquel)
284
Aripiprazole (Abilify)
296
Ziprasidone (Geodon)
238
TEAM (Risp, Lith, DVP)
279
Total
1846
Status of Pediatric Bipolar
Studies and Indications
Double-Blind,
Placebo-Controlled
Studies
Divalproex
Lithium
Oxcarbazepine
Topiramate
Carbamazepine
ER
Risperidone
Olanzapine
Aripiprazole
Quetiapine
Ziprasidone
Open-Label
Studies
Lithium
Carbamazepine
Divalproex
Topiramate
Risperidone
Olanzapine
Aripiprazole
Quetiapine
Ziprasidone
Comparator
Studies
Quetiapine vs.
divalproex
Lithium vs.
Valproate vs
PBO
Green=Indicated
White=Not Indicated
Mood Stabilizers
 Traditional
 Lithium
 Valproate
(Sodium
Divalproex)
 Carbamazepine
 New/Novel







Gabapentin
Lamotrigine
Topiramate
Tiagabine
Oxcarbazepine
Levetiracetam
Zonisamide
Pediatric Lithium Trials
• 4 Older, Crossover
Trials
•
•
Average n = 18
Response Rates 33-80%
• 1 Double-Blind
Placebo Trial
•
Geller et al., 1997
• 1 Discontinuation Trial
•
Lithium Salts
Kafantaris 2004
Pediatric Bipolar
Collaborative Trial (PBC)

NIMH Funded, Multi-Site



CCHMC, Case Western,
Milwaukee Children’s
Double blinded, doubledummy, placebo controlled
Randomized

Monotherapy
 Lithobid, Depakote, Placebo
 2:2:1

6 Months of Treatment


8 Week Acute
16 Week Continuation
 Stimulants for ADHD could
be added

153 Subjects Randomized

Ages 7-17 yr.
Pediatric Bipolar
Collaborative Trial (PBC)

NIMH Funded, Multi-Site



CCHMC, Case Western,
Milwaukee Children’s
Double blinded, doubledummy, placebo controlled
Randomized

Monotherapy
 Lithobid, Depakote, Placebo
 2:2:1

6 Months of Treatment


8 Week Acute
16 Week Continuation
 Stimulants for ADHD could
be added

153 Subjects Randomized

Ages 7-17 yr.
Cohen's D
0.6
0.4
0.2
0.41
0.54
Lith vs PBO
DVP vs PBO
0
Lithium
• FDA Indication
•

Indicated in the treatment of manic episodes of manicdepressive illness > age 12 years
Side effects
 Common
 Weight gain, Exacerbation of Acne, Enuresis, Hypothyroidism
 Uncommon
 Polyuria/Polydipsia, Hair loss, NMS (Haloperidol)

Interactions
 NSAID Increase lithium levels
 Antibiotics (ampicillin, doxycyline, tertacycline…) decrease
renal clearance of lithium and increase level of lithium
Lithium Use
 Target dose of 30 mg/kg/day
 Start outpatients 25 mg/kg/day
 Serum level of 0.9 -1.1 mEq/L
 Onset of action: 7-14 days
 Full efficacy in 6-8 Weeks
 Baseline labs:
 CBC/diif, pregnancy, EKG, renal & thyroid
function, calcium
 Q 6 Months
 Lithium Level, TSH, BUN, serum creatinine
Management of Common Lithium Side Effects
Divalproex Sodium Use in
Children
 Target dose of 20 mg/kg/day
 Start outpatients at 15 mg/kg/day
 Serum level of 80-120 mg/mL
 Onset of action: 7-14 days
 Full efficacy in 4-6 weeks
 Side effects
 Nausea
 Sedation
 Weight gain
 Labs: pregnancy, CBC, platelets, LFTs
 Monitor for Polycystic Ovary Syndrome
(PCOS)
Divalproex/Valproate Side
Effects







Nausea, vomiting, diarrhea
Tremor/Myoclonus
Sedation, mental dulling
Weight gain
Hair loss, decreased platelets
Liver toxicity, pancreatitis, hyperinsulinism, polycystic ovary
syndrome (PCOS)
Black Box Warning
 Hepatotoxicity: Hepatic failure resulting in fatalities has
occurred in patients receiving valproic acid and its derivatives.
Experience has indicated that children under the age of two
years are at a considerably increased risk of developing fatal
hepatotoxicity, especially those on multiple anticonvulsants…
 Pancreatitis:Cases of life-threatening pancreatitis have been
reported in both children and adults receiving valproate.
Carbamazepine
•
Clinical Indications (Adults)
 Acute manic and mixed episodes
• Target serum level
•
•

9-11 g/ml
Many Cytochrome P450 Interactions
Strong association between the risk of developing SJS/TEN with
carbamazepine treatment and the presence of an inherited variant of
the HLA-B gene, HLA-B*1502
 Testing for HLA-B*1502 should be performed in patients with
•
•
ancestry in patients of Chinese ancestry
Side effects
 Dizziness, somnolence, nausea, vomiting, ataxia
Black Box Warning
 “Aplastic anemia and agranulocytosis have been reported in
association with the use of carbamazepine.”
Mood Stabilizer Toolbox
Mood
Stabilizer
Start
at
Target
Serum
Level
Lithium
25-30
mg/kg/day
0.8-1.2
Meq/L
Renal/Thyroid
Function
Valproate
15-20
mg/kg/day
85-110
μg/mL
Liver/Pancreas/ PCOS
Plats.
Hyperammonemia
7-10
μg/mL
WBC/Plats.
Carbamazepine 15-20
mg/kg/day
Monitor
Watch Out
For
Dehydration
toxicity
CYP450
Interactions
Newer Antiepileptic Drug (AEDs)
 Gabapentin
 Topiramate
 Oxcarbazepine
 Lamotrigine
 Levetiracetam
 Tiagabine
 Zonisamide
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A Pilot, Controlled Trial of Topiramate for
Mania in Children and Adolescents With
Bipolar Disorder
 DB, Placebo-controlled
 56 subjects
 Mean age 13.8 ±
2.6 yrs
 48% female
 62% mixed episode
 59% comorbid
ADHD
 Dose
 Mean 278
+121mg/day
DelBello MP, et al. J Am Acad Child Adolesc Psychiatry.
2005;44
Mean Change From
Baseline
F 1,48 = 2.12, P=0.152
A Double-Blind, Randomized, Placebo-Controlled
Trial of Oxcarbazepine in the Treatment of Bipolar
Disorder in Children and Adolescents
 116 Outpatients
 Ages 7-17 yr.
 Bipolar I, Mixed or
Manic
 Double-Blinded, Placebo
Controlled
 Flexibly Dosed
 900-2400 mg/day
 Mean dose 1515
mg/day
 Primary Efficacy Measure
 YMRS
Wagner et al., Amer J Psychiatry July 2006
Lamotrigine
 Blocks voltage-sensitive sodium
channels
 Adults
 2 controlled studies demonstrated efficacy
for bipolar depression
 Indicated for maintenance treatment of
BP I in adults
 Concern: serious rashes/serum sickness
 FDA black box warning
 Not FDA-indicated < Age 16 yrs
Lamotrigine - Rashes & Dosing
 Higher past incidence of rash due to
 Higher initial dosing and faster titration1
 Concomitant VPA administration 1,2
 Definition of serious rash including any
rash leading to discontinuation from trial
2
 Regular tabs available in 25 mg, 100 mg, 150
mg, 200 mg
 Chewable tabs in 2 mg, 5 mg, 25 mg
 Stanford Antigen Precautions by T. Ketter
1Dooley,
J, et al (1996) Neurology 46:240-242
J (2002) J Child Neurology 17:2S34-42
2 Messenheimer,
Revised Lamotrigine Dosing
Initiating lamotrigine in adult bipolar patients:
Not taking drugs known to increase the clearance of lamotrigine* or valproate
Weeks 1 & 2
25 mg/day
Weeks 3 & 4
50 mg/day
Week 5
Week 6
100 mg/day
Target dose
200 mg/day
Taking valproate
Weeks 1 & 2
25 mg/every
other day
Weeks 3 & 4
25 mg/day
Week 5
Week 6
50 mg/day
Target dose
100 mg/day
Taking drugs known to increase the clearance of lamotrigine* and not taking
valproate
Weeks 1 & 2
50 mg/day
Weeks 3 & 4
100 mg/day in
divided doses
Week 5
200 mg/day in
divided doses
Week 6
300 mg/day in
divided doses
Week 7
Target dose up
to 400 mg/day in
divided doses
An Open-Label Study of Lamotrigine Adjunct or
Monotherapy for the Treatment of Adolescents
with Bipolar Depression
CDRS-R
70.00
60.00
50.00
CDRS-R
40.00
Series1
30.00
20.00
10.00
0.00
1
2
3
4
5
6
7
8
9
Week
YMRS
14.00
12.00
10.00
8.00
YMRS
 20 subjects enrolled
 BPI, II, NOS
 Mean Age 15 yr.
 8-week open study
 Weekly assessments: CDRSR, YMRS, CGI-S, OAS-M, CGIC
 Mean final dose = 132 ± 31
mg/day
 Response
 CGI-C: 16/19 (84%)
 CDRS-R: 12/19 (63%)
Series1
6.00
4.00
2.00
0.00
Chang et al. JAACAP March 2006
1
2
3
4
5
Week
6
7
8
9
Atypical
Antipsychotics
1. Aripiprazole (Abilify)
2. Asenapine Maleate (Saphris)
3. Clozapine (Clozaril)
4. Iloperidone (Fanapt)
5. Lurasidone (Latuda)
6. Olanzapine (Zyprexa)
7. Olanzapine/Fluoxetine (Symbyax)
8. Paliperidone (Invega)
9. Quetiapine (Seroquel)
10.Risperidone (Risperdal)
11.Ziprasidone (Geodon)
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A Double-Blind Randomized Pilot Study
Comparing Quetiapine and Divalproex for
Adolescent Mania
 50 Adolescent inpatients
 Bipolar disorder, type I,
mixed or manic
 Mean Age 15+1yr.
 Treatment duration 28 days
 Randomized/DoubleDummy/DB
 Quetiapine 400-600
mg/day
 100-200-300-400
 Valproate 80-120 mg/dl
 (20 mg/kg)
 96% achieved level >
80mg/dl by day 7
DelBello et al. JAACAP March 2006
YMRS
Remission Rates
70
60
50
40
30
20
10
0
60%
28%
DVP
QUE
Risperidone for the Treatment
of acute mania in bipolar youth
• J & J Sponsored
Multisite
• BD I, mixed or manic
• N=166
• 10-17 years old
• Inpatients or
Outpatients
• 3-week DBRCT
• 2 doses of RIS
• 0.5-2.5 mg/day
• 3.0-6.0 mg/day
Adverse Events: Risperidone
in Pediatric Mania
Placebo
0.5-2.5 mg/day
3.0-6.0 mg/day
Response rate
26%
59%
63%
YMRS change,
mean (SD)
9 (11)
19 (10)
17 (10)
8%
5%
25%
Boys 0.6 (7)
Girls 2 (7)
Boys 32 (23)
Girls 50 (46)
Boys 50 (23)
Girls 68 (49)
0%
11%
25%
0.7 (1.9)
1.9 (1.7)
1.4 (2.4)
EPS
Prolactin change,
mean (SD)
Abnormal prolactin
Weight change,
mean kg (SD)
Olanzapine in the Treatment of Acute
Manic or Mixed Episodes in Adolescents
Efficacy
 3 Week, Double-blind,
placebo
 2:1 Randomization
 161 Subjects
 BP I, Mixed or Manic
 Mean Age 15+1.1 yr.
 Age Range 13-17
 Psychotic 18%
 Baseline YMRS 32
 Modal Dose
 9.7+4.5 mg/day
Tohen et al. AJP 2007
Olanz
Placebo
Olanzapine in the Treatment of Acute
Manic or Mixed Episodes in Adolescents
Efficacy
 3 Week, Double-blind,
placebo
 2:1 Randomization
 161 Subjects
 BP I, Mixed or Manic
 Mean Age 15+1.1 yr.
 Age Range 13-17
 Psychotic 18%
 Baseline YMRS 32
 Modal Dose
 9.7+4.5 mg/day
Tohen et al. AJP 2007
Weight ≥
7% of
baseline***
Olanz
Placebo
Weight Gain
Olanz.
N/N (%)
Placebo
n/N (%)
**p Value
44/105
(41.9)
1/54 (1.9)
<.001
Olanzapine 26 Week OpenLabel Extension Treatment
• 146 adolescents with
bipolar I, manic or
mixed
who completed a 3
week double-blind
placebo controlled
study
• Open label olanzapine
(2.5 mg–20 mg/day) for
up to 26 weeks
• Results:
•
Response rate 62.9%
•
≥50% decrease YMRS
and CGI-BP severity ≤3
Fair Use Doctrine,
http://www.copyright.gov/fls/fl102.html
Summary of Atypical Controlled Trials
in Pediatric Bipolar Disorder
Study/
Sponsor
Ref
N
Olanz./
Lilly
Tohen
Am J
Psych.
161
Risper./
Janssan
AACAP
2007
Aripip/
BMS
Duration
(Days)
Dose
(mg/day)
Response
Rate
(YMRS)
Mean
Weight
Gain
(kg)
DBPCRT
2:1
21
10.4
+4.5
49%
3.66
+2.18
BPD I
Manic,
Mixed
DBPCRT
1:1:1
21
0.5-2.5
3-6
59%
63%
1.9
1.4
10-17
BPD I
Manic,
Mixed
DBPCRT
1:1:1
28
10
30
45%
64%
0.9
0.54
M
10-17
BPD I
Manic
DBPCRT
1:1:1
21
400
600
64%
58%
1.7
M
10-17
BPD I
Manic,
Mixed
DBPCRT
2:1
28
80-160
-13.83
(Zipras)
-8.61
(PBO)
-
Sites
Age
Range
Yr.
DX
26
10-17
BPD I
Manic,
Mixed
169
M
10-17
ACNP
2007
296
M
Que/
AstraZeneca
ACNP
2007
284
Zipras/
Pfizer
APA
2008
238
Design
YMRS Change Scores
Atypical Antipsychotics vs. Mood Stabilizers
20
18
16
YMRS Score
14
18.5
17.65
16.5
15.6
14.25
14.2
16.5
13.83
12
10
8
9.99
8.2
11
9.04
9.1
8.61
9
High
6
6
Low
6
4
2
0
Arip
Olanz
Quet
Risp
Zipras
Lith
Val
PBO
Atypical Toolbox
Atypical
Antipsychotic
Start at
(mg/day)
Target
Dose
(mg/day)
Monitor
Aripiprazole
2.5-5
5-20
Weight/Height/BMI
EPS
Olanzapine
5
5-20
Weight/Height/BMI
Weight
(Choles/FAs)
Quetiapine
50-100
300-600
Weight/Height/BMI
Weight
Risperidone
0.35-0.50
1-3
Weight/Height/BMI
EPS/TD/Weigh
t
Ziprasidone
20-40
80-160
Weight/Height/BMI
ECG
Take with food
Assess cardiac
risk factors
Watch Out
For
A Randomized Controlled Trial of Risperidone, Lithium, or Divalproex
Sodium for Initial Treatment of Bipolar I Disorder, Manic or Mixed
Phase, in Children and Adolescents
•
•
•
•
279 antimanic medication–
naive subjects age, 10.1
years; 50.2% female)
100% elated mood and/or
grandiosity, 77.1%
psychosis, 97.5% mixed
mania, 99.3% daily rapid
cycling,
mean (SD) mania duration of
4.9 (2.5) years.
Dosing
• Mean (SD) titrated
lithium level was 1.09
(0.34) mEq/L,
• Mean (SD) divalproex
sodium level was 113.6
(23.0) μg/mL.
• Mean (SD) titrated
risperidone dose was
2.57 (1.21) mg.
Comparisons of end-point Clinical Global
Impressions for Bipolar Illness ImprovementMania (CGI-BP-IM) response rates by medication
Geller, B. et al. Arch Gen Psychiatry
2012;0:Archgenpsychiatry.2011.1508v1-14
Treatment Algorithm for Mania/ Hypomania in
Children and Adolescents
1A: Mixed/Manic
Quetiapine/
Aripiprazole/Risperidone
Stage 1
Monotherapy
1B: Lithium/Valproate/
Olanzapine/Ziprasidone
Negative
response
Evaluate
Positive
response
Continue
Positive response
Continue
Partial response
Stage 2
Augmentation
2: Add mood stabilizer to atypical
or vice versa
Evaluate
Stage 3
2 drug combinations
Partial response
or nonresponse
3: 2 mood stabilizers + 1 atypical or
2 atypicals + mood stabilizer
Kowatch RA et al. Clinical Manual for the Management of Bipolar Disorder in Children and Adolescents. Arlington, VA:
American Psychiatric Publishing, Inc; 2008.
Pediatric BPD Comorbid
Disorders
Disorder
Prepubertal
Adolescent
70-90%
30-60%
20-30%
30-40%
30-40%
30-60%
Oppositional
Defiant Disorder
60-90%
20-30%
Substance Abuse
10%
40-50%
30-40%
30-40%
ADHD
Anxiety Disorders
Conduct Disorders
Learning
Disabilities
Young Children Mania Trial
• Sponsored by the Stanley Research
Foundation
• 6 week, double-blinded, placebo, controlled
• Randomized to:
• Liquid valproate, risperidone or placebo
• 46 Subjects
• Ages 3-7 yr.; mean age 5.5 yr
• ~70% Caucasian
• ~60% Male
• DSM-IV Criteria for Bipolar Disorder I, Mixed
or Manic Episode, Current
Family History in Mother or
Father
70
60
60
50
40
%
28
30
23
20
9
10
0
BPD
MDD
ADHD
Schizophren
Young Mania Rating Scale
35
RSP
Dival
30
PCB
25
20
p=0.00
8
15
10
B
6
1
2
3
Week
4
5
Prolac n Levels
52.91
7.43
5.25
Val
8.76
Baseline
6.92
5.11
Risp
Week 6
PCB
Guidelines: How Long to
Treat?
• The Consensus of Opinion Was That
Medication Tapering or Discontinuation Be
Considered If the Patient Has Achieved
Remission for a Minimum of 12-24
Consecutive Months
• For Less Severely Ill Patients, or in
Patients for Whom a Diagnosis Is Less
Clear, a Briefer Treatment Period May
Be Indicated
CABF Guidelines 2006
• 115 Children
• Enrolled 1995-1998
• First Episode Bipolar I
• Ages 7-16 yr.
• Elation and/or
Grandiosity
• Retention Rate 94%
• Assessed
• 6, 12, 18 months
• 2, 3, 4, 5, 6, 8 yr.
• Treated in community
• After Reaching Age 18 yr.
• 115 Children
• Enrolled 1995-1998
• 54 Subjects
• First Episode Bipolar I
• Mean Age 20.6+1.8 yr
• Ages 7-16 yr.
• Outcome
• Elation and/or
Grandiosity
• 44% BPD I
• Retention Rate 94%
• 30% Depressive
• Assessed
Disorder
• 6, 12, 18 months
• 35% SUD
• 2, 3, 4, 5, 6, 8 yr.
• Treated in community
Pediatric Bipolar Summary
 Difficult to recognize and
manage
 More Research Is Needed
 Single Agents
 Combination
Pharmacotherapy
 Pharmacotherapy + DBT
 Recurrent Disorder That
Requires Psychosocial
Therapy &
Pharmacotherapy
 We are making progress
Fair Use Doctrine,
http://www.copyright.gov/fls/fl102.html
Course of Illness &
Psychosocial Treatment of
Bipolar Disorder in Children
Mary A. Fristad, PhD, ABPP
Professor, Psychiatry, Psychology & Nutrition
Director, Research & Psychological Services
Division of Child & Adolescent Psychiatry
The Ohio State University’s Wexner Medical Center
Just Because thI’m Bipolar
14 Year Old 8 Grader
Former MF-PEP Study Participant
Just because I’m bipolar
I’m not a freak
I’m not weird
I just want to be noticed
Just because I’m bipolar
I still have feelings
I still have emotions
I just have trouble expressing them
Just because I’m bipolar
I can still be trusted
I can still be reliable
Just because I’m bipolar—I’m still a normal kid
Conflict of Interest/Funding
 Dr. Fristad receives royalties from
 CFPSI: MF-PEP and IF-PEP Workbooks
 Guilford Press:
 Raising a Moody Child: How to Cope with
Depression and Bipolar Disorder
 Psychotherapy for Children with Bipolar and
Depressive Disorders
 APPI:
 Clinical Manual for Management of Bipolar
Disorder in Children and Adolescents
 Children’s Interview for Psychiatric
Syndromes (ChIPS)
When Will My Child Get Better...?
The MDD Picture
Birmaher et al, 96
 Single episode length: 7-9 months
 90% get well by 1.5-2 years
 6-10% stay impaired
 Recurrence
 40%, 2 yrs
 70% 5 yrs
When Will My Child Get Better?
The DD Picture
Kovacs et al, 94
 Single untreated episode: 4 years
 MDD episode usually comes 2-3 years after
DD onset
 Can lead to:
 Bipolar disorder: 13%
 Substance abuse: 15%
Early Age of Onset Linked to
Longest Delay to Treatment
Leverich et al (2007) J Ped 150: 485-490
18
480 outpts w/ BPD
retrospectively
rated for onset and
prospectively
followed for one
year
16
14
12
10
8
6
4
2
Yrs Delay to First
Treatment
0
< 12
13-18
19-29
30+
Adults—BPD
Rea et al, JCCP, 2003
 UCLA study, N=53: delays rehospitalization
1.0
0.8
0.6
0.4
0.2
Individually-focused treatment
Family-focused treatment
0.0
0
26
52
78
104
Weeks
130
156
182
Mood Symptom Scores
Does Expressed Emotion Predict Mood Symptom
Scores Over 2 Years Among Adolescent Bipolar
Patients (N=20)?
(Miklowitz et al., 2006; Dev and Psychopathology)
2.6
2.4
2.2
2
1.8
1.6
1.4
1.2
1
High-EE
Low-EE
0
3
6
9
12
Time (Months)
F(1, 17) = 6.33, p = .02; Cohen’s d = 0.98
18
24
Psychosocial Impact on Course of
Illness Geller et al, 2000; 2002; 2004
 At baseline, families of youth with BPD,
compared to healthy and ADHD control
groups:
 Less warmth
 Greater tension and hostility
 At 2 and 4 year follow-up,
 Lower maternal warmth predicted faster relapse
after recovery from mania
 Intact families associated with faster rate of
recovery
 Medication status was not predictive of illness
course
Empirically Supported Psychosocial
Adjunctive Treatments for Childhood
Bipolar Disorder
 Fristad, Goldberg-Arnold & Gavazzi, 1999
Bipolar Disorders
-None
Current Psychotherapies for
Youth with Bipolar Disorder
 CBT/Family Systems Based
 Pavuluri/West—RAINBOW program
 Miklowitz-FFT-A
 PEP (MF-PEP, IF-PEP)
 DBT—T. Goldstein
 IP-SRT--Hlastala
How to Conceptualize
Family-Based Intervention
 Historically, families
 Have been blamed
 Have not gotten useful
information/support/skill building
 This can result in families being “skittish”
or “defensive” about family-based
intervention
Goals of Psychoeducation
 Teach parents and children about
 The child’s illness & its treatment
 Provide support
 Peers (“I’m not the only one”)
 Professionals - understand the disorder
 Build skills
 problem-solving
 communication
 symptom management
Our Motto
 It’s not your fault, but it’s your challenge!
ODMH Study
Fristad, Goldberg-Arnold & Gavazzi, JMFT, 2003
 35 children and their parents
 54% depressive; 46% bipolar disorders
 M=3.6 comorbid diagnoses/child
(range, 1-7)
 C-GAS=51 at baseline
 29/35 (83%) on meds
 8-11 years old (average, 10.1 yrs)
 77% boys
 6 month wait-list design
 6 sessions, 75 minutes/session, manualdriven treatment
ODMH Findings
Fristad, Goldberg-Arnold & Gavazzi, JMFT, 2003
 Parents






Increased knowledge of mood disorders
Increased positive family interactions
Increased efficacy in seeking treatment
Improved coping skills
Increased social support
Improved attitude toward child/treatment
 Children
 Increased social support from parents
 Increased social support from peers (trend)
Multi-Family Psychoeducational
Psychotherapy (MF-PEP)
Fristad, Verducci, Walters & Young (2009) Arch Gen Psych, 66(9): 1013-1021
 Children aged 8-11 (any mood disorder)
 8 sessions, 90 minutes each
 Begin/end with parents/children together
 Middle (largest) portion-separate groups
Children receive in vivo social skills
training (in gym) after formal
“lesson” is completed
 Therapists: 1-parents; 2-children
 Families receive projects to do between
sessions
8 Session Outline - Parents
1.
2.
3.
4.
5.
6.
7.
8.
Welcome, symptoms & disorders
Medications
“Systems”: school/treatment team
Negative family cycle, WRAP-UP 1st ½
Problem solving
Communication
Symptom management
WRAP-UP 2nd ½ of program & graduate
8 Session Outline - Children
1.
2.
3.
4.
5.
6.
7.
8.
Welcome, symptoms & disorders
Medications
“Tool kit” to manage emotions
Connection between thoughts,
feelings and actions
(responsibility/choices)
Problem solving
Nonverbal communication
Verbal communication
Review & GRADUATE!
Demographics—Various Samples
Variable
Treated BPD
n=89
Age
BPD-ITT
n=115
9.8
% Male
72
69
% White
91
94
% Fam Hx-Mania
53
55
% Fam HxDepression
% Fam Hx-Either
73
72
84
83
9.7
NIMH Study Design, N=165
Groupa
Time 1
Month 0
Time 2
Month 6
Time 3
Month 12
Time 4
Month 18
MF-PEP Baseline:
Follow-up Follow-up
Follow-up
+ TAUb Pretreatment
WLC + Baseline
Follow-up PreFollow-up
treatment
TAUc
aFamilies were enrolled in 11 sets of 15 (7-MFPG/8-WLC) = 165
families
bMulti-Family Psychoeducational Psychotherapy + Treatment As
Usual
cWait-List Control + Treatment As Usual
Outcome Measure
 MSI=Mood Severity Index
 CDRS-R + MRS (equal contributions)
 <10: minimal symptoms
 11-20: mild symptoms
 21-35: moderate symptoms
 >35: severe symptoms
Mood Severity Index (Parent, Current)
MF-PEP BPD Sample
 N=115, all BPD
 Pre-post Imm=WLC
25
20
18
M
os
12
M
os
M
6
os
15
e
 Χ2=6.19, p<.02
 Slope
difference=
-7.76/12 mos
30
as
el
in
 Linear Mixed Effects
Modeling
35
B
 n=55 Immediate
 n=60 Wait List
Immediate
Dr. Fristad--R01 MH61512
Wait List
Mood Severity Index (Parent, Current)
MF-PEP Treated BPD Sample
 N=89
 Pre-Post Imm=WLC
25
20
18
M
os
12
M
os
M
6
os
15
e
 Χ2=5.91, p<.02
 Slope
difference=
-7.96/12 mos
30
as
el
in
 Linear Mixed
Effects Modeling
35
B
 n=54
Immediate
 n=35 Wait List
Immediate
Dr. Fristad--R01 MH61512
Wait List
Impact of MFPG on Service
Utilization & Mood Severity
Mendenhall, Fristad & Early, 2009, J Cons Clin Psychol
 Parental attitudes toward treatment
changes with MF-PEP; impacts quality
of services sought
 Improved quality of services leads to
better mental health outcomes
 MF-PEP appears to improve quality of
services utilized & child’s mood severity
over time as designed to do. It helps
parents become better consumers.
Anecdotal Evaluations-Parents
 No matter how bad the situation is…there is
hope and treatment. Don’t give up. This
program was an eye opener for me. I also was
encouraged and relieved to find out that I was
not alone.
 Listen to what they are saying. They can really
help you. Learn what is going on with your
child. Stay focused on what is going with your
child and do not give up on your child.
Anecdotal EvaluationsChildren
 You get to meet new people you never knew
before. They help you with your symptoms.
 They’re nice and they’re helpful. And you guys
support us and give us snacks. You’ve been
nice to us and treated us with respect.
 It really helps out if you let it.
Efficacy-to-Effectiveness Trial
MacPherson, Fristad, et al, ABCT, ‘08,’09, ‘10, KS
Conference ‘10
 Parent Findings:
 ↑ knowledge of mood disorders
 ↑ satisfaction with treatment
 Child Findings:
 ↑ satisfaction with treatment
 Referring Therapist Findings:
 ↑ satisfaction with MF-PEP
 ↑ agreement with MF-PEP goals/concepts
 ↑ parental knowledge and coping
 smooth transition to usual care
 discussion of MF-PEP content by family in
therapy sessions
 intention to refer future families to MF-PEP
Efficacy-to-Effectiveness Trial
MacPherson, Fristad, et al, ABCT, ‘08,’09, ‘10, KS
Conference ‘10
 Treating Therapist Findings:
 positive experience and general satisfaction
with training in and implementation of MFPEP
 interested in running future MF-PEP
 Preliminary results support the
transportability and acceptability of the
intervention
Individual-Family Psychoeducation
(IF-PEP) OH Dept Mental Health, 2002-2004
 N=20
 16 sessions
 Alternate child and parent with parent
 Same content + Healthy Habits
diet, exercise, sleep
 Comparable design to MFPG
IF-PEP Primary Outcome:
MSI-Parent-Cur—Power Analyses
Variable
N per Condition
Effect Size
MSI-Parent-CUR
T1-T2
64
.45
MSI-Parent-CUR
T1-T3
36
.60
40
MSI-P-Cur
35
30
25
20
15
Baseline (T1)
6 Mos (T2)
Imm n=6
WLC n=7
12 Mos (T3)
IF-PEP: Parent Evaluations
 Anonymous evaluations completed after
treatment
 Parents report (1-5 rating, overall 1.6)
 ↑ knowledge re: symptoms, medication,
accessing treatment
 ↑ skills re: working with schools and
treatment team, managing symptoms at
home
 Feeling supported/not blamed
IF-PEP: Children’s Evaluations
 1-5 Rating Scale
 Overall rating, 1.7
 Item Range: 1.3 (therapist) to 2.2 (learned
about medications)
 ↑ knowledge re: mood symptoms, medication
 ↑ ability to get along with family, friends and at
school
 ↑ skill re: symptom management
 ↑ support/ ↓ isolated, “not the only one”
 parents’ behavior toward them better
IF-PEP 24: Two Case Studies
Leffler, Fristad & Klaus, 2010, J Fam Psychotherapy
 Expanded from 16 to 24 sessions
 1 sibling session
 1 additional systems-of-care (school,
mental health) session
 1 school professionals session (face-toface or conference call attendance)
 2 Healthy Habits sessions
 3 additional “in-the-bank” sessions
IF-PEP 24: Case Studies
Leffler, Fristad & Klaus, 2010, J Fam Psychotherapy
 11 yr old girl “Jane”
 Long treatment history
 sertraline, 3 mos: akathesia, elevated mood,
dangerous behaviors
 divalproex sodium, clonidine, quetiapine,
ages 9-11: no significant improvement
 fluvoxamine and clonazapam: for
compulsive behavior and agitation
 School and private therapeutic support
IF-PEP 24: Case Studies
Leffler, Fristad & Klaus, 2010
 10 yr old boy “John”
 Extensive treatment history
 2 yrs, divalproex sodium (trial of
methylphenidate)
 4 yrs, risperidone
 6 yrs, atomoxetine
 8 yrs, trials of methylphenidate,
amphetamine/dextroamphetamine, clonidine,
lithium, and aripiprazole
 9 yrs, trials of quetiapine and escitalopram
 10 yrs, oxcarbazepine
 very significant weight gain
 Extensive psychotherapy history
Jane’s Diagnoses
Leffler, Fristad & Klaus, 2010
 BP-1: Most Recent Episode Mixed: current
moderate to severe symptoms: dysphoric
mood, irritability, psychomotor agitation,
increased appetite, strong craving for sweets,
weight gain, rejection sensitivity, irritability,
motor hyperactivity, derailment, mood lability
 ADHD-Combined
 ODD
 GAD
 OCD
John’s Diagnoses
Leffler, Fristad & Klaus, 2010
 BP-1 Most Recent Episode Hypomanic:
 current mild symptoms: irritability,
negative self-image, elevated mood,
uninhibited people seeking, hypersexuality
 ADHD-combined
 ODD
 Specific Phobia-dark & heights
 SAD
Jane’s Treatment
Response
Measure
Pre
Post
Change
C-GAS: Current
36
48
Improved
C-GAS: Worst
31
41
Improved
KMRS
45
28
Improved
KDRS
67
55
Improved
TBQ-P
3.9
4.2
Improved
John’s Treatment
Response
Measure
Pre
Post
Change
C-GAS: Current
35
40
Improved
C-GAS: Worst
15
38
Improved
KMRS
48
28
Improved
KDRS
43
55
Worsened
TBQ-P
3.3
4.2
Improved