Juvenile Depression
Jeff Q. Bostic, M.D., Ed.D.
Massachusetts General Hospital
Harvard Medical School
Disclosure Statement
Relationship/Role
Research Grant:
Speaker’s Honoraria:
Commercial Enterprise(s)
Glaxo Wellcome
Eli Lilly
Forest
Pfizer
Smith-Kline
Abbott
Glaxo-Wellcome
Forest
AACAP Policy Statement 2000

Most psychoactive agents lack FDA
approval
 “In making decisions to prescribe such
medications the physician…should:
• Consider data from studies in adults in
treating the target disorder
• Any clinical or anecdotal reports of use in
child and adolescent patients,
• Studies conducted outside the United States
• And the experience of colleagues.”
(AACAP Council , 2000)
How Significant is
Depression?
Depression or Dysthymia = 17%
Most people in 20’s, >50% by age 40
By adolescence ~ 8%, girls > boys 2:1
Depression > all age groups
But leveled
off in 1988,
andyouth
began
Suicide
quadrupled
among
since 1950 in 1994
decreasing
Assessment of Mood Disorders

Internalizing Symptoms: Children
(Mood, Guilt/Criticism, Anhedonia)

Externalizing Symptoms: Parents, Teachers
(Withdrawal, Appetite, Sleep)

Rating Scales
(Beck Depression Inventory, Children’s
Depression Inventory: low specificity)

Biological Markers: None yet
Assessment of Suicidality
 Explore
with patient, family, friends,
teachers
 Inquire about previous thoughts and
attempts
 Identify “reasons for living”
 Distinguish suicidality from selfmutilation
 Determine access to means of suicide
(remove weapons, particularly guns)
Bipolar “Switching” Predictors

Family History of Bipolar
Disorder
 Psychomotor Retardation rather
than Agitation
 Psychosis
 Hypersomnia
 Rapid Onset of Depression
(Bowden & Rhodes, Psychiatric Annals, 26 suppl: 430-434, 1996)
Juvenile Mood Disorders
Bostic, 2003
3 Domains of Child Function
Family
Friends
School
Indications for Antidepressants

Depression Impairs Multiple
Domains

Recurrent Depressive Episodes

Unwilling to Undergo Psychotherapy

Depression + Psychosis

Bipolar Depression
Controlled TCA Trials: Children
STUDY
N
AGENT
Petti & Law,
1982
Kashani, 1984
6/6
Imipramine
66
33
9/9
Amitriptyline
66
22
Preskorn, 1987
22
Imipramine
70
NA
Puig-Antich,
1987
Geller, 1989
46/38
Imipramine
56
68
60/50 Nortriptyline
31
17
Hughes, 1990
31/27
46
50
Imipramine
Drug Pbo
Controlled TCA Trials: Adolescents
STUDY
N
AGENT
Drug
Pbo
Kramer, 1981
20
Amitriptyline
80
60
Geller, 1990
31
Nortriptyline
8
21
Klein, 1990
30
Desipramine
60
40
Kutcher, 1994
42
Desipramine
48
35
Kye, 1996
22
Amitriptyline
75-92
30-90
Birmaher, 1998
27
Amitriptyline
70
70
Controlled TCA Trials: Adolescents
STUDY
Desipramine
in Adolescents
2001
N
AGENT
Drug
•Controlled
aged 13 –19
Kramer,
1981 Trial,
2030 Pts,Amitriptyline
80
•Mexico City National Institute of Psychiatry
Pbo
60
Geller, 1990
31
Nortriptyline
8
21
Klein, 1990
30
Desipramine
60
40
Amitriptyline
75-92
30-90
Amitriptyline
70
70
•Dosing: 150mg/d for 10 wks
•Ratings weekly with Beck and Depression Self Rating
Scale 1994
Kutcher,
42
Desipramine
48
35
•DMI: 57% responded
Kye, 1996
22
•PBO: 54% responded
Birmaher, 1998
27
•SE: DMI > PBO (p=0.015)
Cochrane Review of TCAs in
Pediatric MDD
 Thirteen RCTs involving 506 participants aged 618 years
 No overall improvement with treatment
compared to placebo
 Small advantage for TCAs in adolescents, but
not children
 Treatment with a tricyclic caused more vertigo,
orthostatic hypotension, tremor and dry mouth
 CONCLUSION: TCAs are ineffective
Hazell, P et al (2002). Tricyclic drugs for depression in children and
adolescents. Cochrane Database Syst Rev(2), CD002317.
Juvenile Mood Disorders
Bostic, 2001
TCA’s in Juveniles

6 DB, PC trials in children
 5-9% benefit over placebo

7 DB, PC trials in adolescents
 8-14% benefit over placebo
Serotonin Reuptake Inhibitors
(SRI’s)
 Fluoxetine
(Prozac)
 Sertraline (Zoloft)
 Paroxetine (Paxil)
 Citalopram (Celexa);
Escitalopram (Lexapro)
 Fluvoxamine (Luvox)
Controlled Fluoxetine Trials:
Juvenile MDD
STUDY
N
AGENT
Drug Pbo
Simeon, 1990
40 Fluoxetine
66
66
Emslie, 1997
96 Fluoxetine
56
33
Emslie, 2002
219 Fluoxetine
65
53
Emslie et al., 97, 02
Emslie, G. et al. (1997). Archives of General Psychiatry, 54(11), 1031-1037.
Emslie, G. et al. (2002). J Am Acad Child Adolesc Psychiatry, 41(10), 1205-1215.
Decrease in CDRS (Baseline > 40)
Baseline
Wk 1
Wk 2
Wk 4
Wk 6
Wk 8
0
-5
-10
-15
-20
-25
Fluoxetine '97
Placebo '97
Fluoxetine '02
Placebo '02
SSRIs and Growth Suppression
4
Pts (1 F), age 11-14, with OCD
or Tourette’s
 Fluoxetine 20-80mg/d or
Fluvoxamine 50-100mg/d
 Growth deceleration on SSRI,
reversed off SSRI
(Weintrob et al., Arch Pediatr Adolesc Med, 156:696, 2002)
Double-Blind Paroxetine Trials:
Juvenile MDD
STUDY
N
AGENT
Keller,
2001
275
Paroxetine
66
48
Imipramine
52
48
Paroxetine
65
--
Clomipramine
48
--
Braconnier,
2003
121
Drug Pbo
Paroxetine in Pts < 18
(Washington Post, 6-11-03)
Paroxetine (Seroxat; Paxil) “increase in rate of
self-harm and potentially suicidal behavior in this
age group” Medicines & Healthcare Products Regulatory Agency
1385 pts in 9 studies: Juvenile MDD (n= 663; 8-12 wks,
10-50mg/d), OCD (n=400), Social Anxiety (n=322)
•Treatment + Taper + 30-day followup
33 showed signs of mood swings that included
suicidal thinking and suicide attempts
•1.2% PBO (n=8) vs. 3.4% (n=25) in PRX Group
Keller et al., 2001
Keller, M. (2001). J Am Acad Child Adolesc Psychiatry, 40(7), 762-772.
Hamilton Depressed Mood Score
3
2.5
2
1.5
p = .001
1
0.5
Baseline
Endpoint
Paroxetine
Imipramine
Placebo
Keller et al., 2001
Keller, M et al (2001). J Am Acad Child Adolesc Psychiatry, 40(7), 762-772.
Hamilton Depression - 17 Item Scores
20
16
12
8
p = .13
4
En
d
6
W
k
4
W
k
2
k
W
Ba
se
l
in
e
0
Paroxetine
Imipramine
Placebo
Sertraline in Juvenile Depression
Wagner, K. (2002). Sertraline in Pediatric Major Depression. Paper presented at the Annual
Meeting of the American Psychiatric Association, Philadelphia, Pennsylvania.
 DB, PC Trial, 10 wks
 376 Pts: 177 aged 6-11; 199 aged 12-17
 56 sites: US, Canada, Costa Rica, Mexico,
Brazil
 Dose: 102 mg/d kids, 133mg/d teens
 Side Effects: Diarrhea (11%), Vomiting
(9%), Anorexia (7%), Agitation (7%)
 Discontinuation: 9% SRT v. 2% Pbo
Wagner et al., 2002
Wagner, K. (2002). Sertraline in Pediatric Major Depression. Paper presented at the Annual
Meeting of the American Psychiatric Association, Philadelphia, Pennsylvania.
Child Depression Rating Scale (> 40)
Baseline
Wk 1
Wk 2
Wk 4
Wk 6
Wk 8
Wk 10
0
-5
-10
-15
Sertraline
Placebo
-20
p < .05
-25
-30
-35
Citalopram in Juvenile
Depression
Wagner et al., 2001
•DB, PC, 8 Weeks
•174 Pts: 83 aged 7-11; 91 aged 12-17
•Dose: 23mg/d children; 24mg/d adolescents
•Side Effects: Nausea (14%); Rhinitis (14%)
•Discontinuation: 5.9% (CIT) v. 5.6% (PBO)
Wagner et al., 2001
Wagner, K. (2001). Presented at the Annual Meeting of the College of
Neuropsychopharmacology, San Juan, Puerto Rico.
Child Depression Rating Scale (> 40)
Baseline
Wk 1
Wk 2
Wk 4
Wk 6
Wk 8
0
-5
-10
Citalopram
Placebo
p < .05
-15
-20
-25
p < .01
Juvenile Depression:
Citalopram

Of those who responded to CIT, 71%
had failed previous SSRI’s
 8/10 with comorbid depression and
anxiety responded
 Comorbid ADHD:
 6/7 with MDD + ADHD responded
 5/6 with Anxiety + ADHD responded
Bostic et al (2001). J Child Adol Psychopharm, 11:159-166.
Atypical Antidepressants
Venlafaxine (Effexor)
Nefazodone (Serzone)
Mirtazapine (Remeron)
Bupropion (Wellbutrin)
Controlled Venlafaxine Trials:
Juvenile MDD
Mandocki MW et al (1997). Psychopharm Bull, 33:149-154
STUDY
N
AGENT
Drug Pbo
Mandocki,
1997
33 Venlafaxine ~50
~50
Venlafaxine in Pts < 18
(Wyeth Prescribing Letter, 8-22-03)
(Effexor IR/XR) “In pediatric clinical trials, there
were increased reports of hostility and, especially
in Major Depressive Disorder, suicide-related
adverse events such as suicidal ideation and self
harm.”
In Pts (6-17) in GAD and MDD trials, no efficacy:
•Hostility: 2% VFX XR v. < 1% PBO
•Suicidal Ideation: 2% VFX XR v. 0% PBO
•No actual suicides in these clinical trials
Controlled Juvenile Studies
Nefazodone

195 Pts with MDD (99 NFZ v. 96
Pbo)
 Age: 12-17, treated 8 weeks
 Dosing: 100-600mg (x=444mg/d)
 Dropouts: 27%
(Emslie et al., Presented at NCDEU, 2002)
Nefazodone
70
60
50
40
p=.055
30
20
10
0
Wk 1
Wk 8
NFZ
PBO
Controlled Juvenile Studies
Mirtazapine

250 Pts with MDD (165 MTZ v. 65
Pbo)
 Age: 7-17, treated 8 weeks
 Dosing: 15-45mg
 Dropouts: 5%
(Emslie et al., Presented at the 48th Annual AACAP Meeting, 2001)
Mirtazapine
70
60
50
40
MTZ
PBO
30
20
10
0
Wk 1
Wk 8
Juvenile Depression:
Bupropion SR (Wellbutrin; Zyban)
Open Trial of 10 weeks (+ 2wks SB Pbo)
24 patients with ADHD + MDD or
dysthymia
Dosing: 2.7mg/kg/am and 1.7mg/kg/pm
Significant improvement by teacher &
parent ratings
Daviss B et al (2001). J Am Acad Child Adolesc Psychiatry, 40:307-314.
Juvenile Depression:
Bupropion SR (Wellbutrin; Zyban)
88% Pts much improved depression
63% Pts much improved ADHD
Side effects < 10% except rash 13%
which resolved while on BPN (nausea
13% during PBO run-in phase)
Daviss B et al (2001). J Am Acad Child Adolesc Psychiatry, 40:307-314.
Maintenance Treatment
•
Remind Pt and Family of symptoms
suggesting recurrence
• See Pts every 2-4 months over next 8
months (Emslie et al., 1997)
• If > 2 episodes, 95% chance
recurrence (so continue Rx)
• Taper other Rx first (e.g., neuroleptic)
Cognitive-Behavioral Therapy

6 controlled trials in 165 juveniles

Efficacy: 62% vs. 36% (placebo)

Limitations:
 Less benefit in children < 13 years old
 Often reports with Group Sessions
 Self-Report Measures
 Dysphoria rather than MDD
TADS
Treatments for Adolescents With
Depression Study
PI: John S. March, MD, MPH
March J et al (2003). J Am Acad Child Adolesc Psychiatry, 42:531-541.
Purpose of TADS
To examine the effectiveness,
including cost effectiveness, of
medication (fluoxetine) and cognitivebehavioral psychotherapy, alone and
in combination, for the acute and
long-term treatment of adolescents
with DSM-IV Major Depression
Juvenile Depression: Summary
 Depression
may manifest differently in
Juveniles
 Consider Functional Impairment as
Plan Treatment
 Antidepressants: SRI’s have most
support to date
 CBT has support
 CBT +/- Antidepressants being studied
Juvenile Bipolar Disorder
Sandra DeJong, M.D., & Jeff Q. Bostic, M.D., Ed.D.
Massachusetts General Hospital
Harvard Medical School
Juvenile Bipolar Disorder



93 Pts, aged 6-16
Compared with 81 ADHD Pts, 94 controls
Symptomatically, BP Pts had:
 Mixed mania: 55%
Rapid Cycles: 87%
 Psychosis: 60%
Grandiose delusions: 50%
 Suicidality: 25%
 Recovery: 15% by 6 months, 37% 1 yr, 56% 18 months

Functioning: More likely to have impaired maternalchild warmth, parental-child tension, impaired peer
relationships
(Geller et al., 2001)
Prepubertal & Early Adolescent
Bipolar Disorder
Type of Cycles
Prepubertal
N=53
Pubertal
N=40
Rapid
(4 cycles/yr)
0
0
Ultrarapid
(5-364 cycles/yr)
4% (2/53)
18% (7/40)
Ultridian
81% (43/53)
(>364 cycles/yr)
73% (29/40)
Geller, et al., JCAP 10:157-164, 2000
Bipolar Disorder:
Symptoms

~98% ADHD Dx prior to Mania

Unprovoked, unpremeditated aggression
(Wozniak et al., 1994)

Tired in am, but then tantrums lasting
30min – 7 hrs
 Energy accelerates over day, peaking pm
 Nightmares of attack or abandonment
(Papolos, 2000)
Pediatric-Onset Bipolar Disorder:
Comorbid Conditions
ADHD
Bipolar
Percent
88
90
80
70
60
50
40
30
20
10
0
56
48
37
26
16
15
0
Psychosis
Mult Anx
Conduct
ODD
Wozniak, J. data presented at MGH ADHD Course March 7-9, 2003 Boston, MA
ADHD and BPD: Results from
4-Year Follow-Up Study
30
Overall rate of Bipolar Disorder
p<0.01
25
% of group
p<0.01
20
15
ADHD
Control
p<0.01
10
5
0
Baseline
Year 1
Year 4
Biederman J, et al. Arch Gen Psychiatry 53:437-46, 1996
Improvement of ADHD Before and After
Improvement of Manic Symptoms
The probability of ADHD improvement was 7.5 times higher
following initial improvement in manic symptoms
% of visits improved
25
20
Odds Ratio = 7.5 (1.1-52.2)
p<0.04
15
10
5
0
Before
After
Do SRIs Destabilize
Manic Symptoms?

SRIs in children with a history of mania but
no active manic symptoms significantly
predicted deterioration of manic symptoms.
 Subjects receiving an SSRI were three times
as likely to develop manic symptoms at the
next follow-up visit compared to subjects
who had not received an SSRI
(RR = 3.0 (1.2-7.8); p=0.02).
(Biederman et al., JCAP 10 (3):185-192, 2000)
Bipolar Disorder:
Rx Treatment Course

42 Juveniles (x=11yrs) with Mania (71% also
ADHD)




Randomized to VPA, Li, or CBZ for 6 wks
CGI and 50% reduction on Young Mania Scale
53% VPA responded vs. 38% Li, 38% CBZ
VPA Pts “worse” first 2-3 wks, CBZ fastest
response
(Kowatch et al., JAACAP 39:713-720, 2000)
Juvenile Mania: Risperidone
(Frazier et al., 1998)
MEAN CGI SEVERITY (N = 28)
7
Severe
6
Pre-treatment
p<.01
Post-treatment
5
Moderate
p<.01
p<.001
4
3
Mild
2
1
Mania
ADHD
(N=28)
(N=25)
Psychosis Aggression
(N=13)
(N=28)
Open Trial of Olanzapine in Juvenile
BPD (Frazier et al., JCAP 2001)
Young Mania Rating Scale
Mean Change to Endpoint
Baseline:
0
Children’s Depression Rating Scale
30.70
44.57
-5
-10
-15
-20
-14.22 ***
-19.04 ***
***p < .001
There was a significant improvement in Young Mania Rating
Scale Total scores from baseline to endpoint following
olanzapine treatment.
Olanzapine in Pediatric Bipolar Disorder:
Open Label, 8 - Weeks, n=23
CGI-BP Severity of Overall
Illness Scale: Weekly Change
0
1
2
3
4
5
6
0.0
-0.5
-1.0
from Baseline (LOCF)
p<0.001
-1.5
-2.0
-2.5
Weight Gain (Kg)
Weekly Change From Baseline
(LOCF)
Frazier et al, JCAP, 2001
Week, Post-Baseline
7
8
Quetiapine

Psychosis




10 Pts, aged 12-15
Open label, followed 10 wks
25-800mg/d
Well-tolerated, effective, pharmacokinetics similar
to adults
(McConville et al., J Clin Psychiatry 61:252-260, 2000)

Bipolar Augmentation




30 Pts, aged 12-18
DB: VPA + QTP vs. VPA + PBO
20mg/kg/d VPA + 450mg QTP
87% VPA + QTP vs. 53% VPA + PBO
(DelBello et al., JAACAP 41:1216-1223, 2002)
Combination Mood Stabilizer + Neuroleptic
Treatment for Juvenile Bipolar Disoerder

Lithium + Neuroleptic
 42 Pts, aged 12-18 with BPD + Psychosis
 Open Label, 4 wks with Lithium +
Haloperidol, Risperidone, Olanzapine,
Quetiapine, Thiothixene,
Chlorpromazine
 64% improved on both, but after
neuroleptic taper “few” maintained
response
(Kaftanaris et al., JCAP 11:409-413, 2001)
Dosing of Antypical Antipsychotics:
Juvenile Bipolar Disorder
Agent
Initial (mg) Target (mg/d)
Risperidone
0.25-0.5
0.25-10
Olanzapine
2.5
5-20
Quetiapine
25
25-800
Ziprasidone
20
20-160
Aripiprazole
5-10
5-30
Juvenile Bipolar Disorder: Summary
 Manic
episodes short and frequent
compared to adults
 Mood Stabilizers appear less effective
in younger patients
 Atypical Neuroleptics increasingly 1stline treatment, alone or with Mood
Stabilizers
 Awaiting controlled data to compare
specific agents for efficacy and side
effect differences