Juvenile Depression

Jeff Q. Bostic, M.D., Ed.D.Massachusetts General Hospital

Harvard Medical School

Disclosure StatementDisclosure Statement

Relationship/Role Commercial Enterprise(s)Relationship/Role Commercial Enterprise(s)

Research Grant:Research Grant: Glaxo WellcomeGlaxo Wellcome

Eli LillyEli Lilly

ForestForest

PfizerPfizer

Smith-KlineSmith-Kline

AbbottAbbott

Speaker’s Honoraria:Speaker’s Honoraria: Glaxo-WellcomeGlaxo-Wellcome

ForestForest

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 40By adolescence ~ 8%, girls > boys 2:1

Depression > all age groupsSuicide quadrupled among youth

since 1950

But leveled off in 1988, and began decreasing in 1994

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 self-

mutilation 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 DisordersBostic, 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 Drug Pbo Petti & Law, 1982

6/6 Imipramine 66 33

Kashani, 1984 9/9 Amitriptyline 66 22

Preskorn, 1987 22 Imipramine 70 NA

Puig-Antich, 1987

46/38 Imipramine 56 68

Geller, 1989 60/50 Nortriptyline 31 17

Hughes, 1990 31/27 Imipramine 46 50

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 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

Desipramine in Adolescents 2001Desipramine in Adolescents 2001

•Controlled Trial, 30 Pts, aged 13 –19

•Mexico City National Institute of Psychiatry

•Dosing: 150mg/d for 10 wks

•Ratings weekly with Beck and Depression Self Rating Scale

•DMI: 57% responded

•PBO: 54% responded

•SE: DMI > PBO (p=0.015)

Cochrane Review of TCAs in Pediatric MDD

Thirteen RCTs involving 506 participants aged 6-18 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 DisordersBostic, 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, 02Emslie, 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)

-25

-20

-15

-10

-5

0Baseline Wk 1 Wk 2 Wk 4 Wk 6 Wk 8

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 Drug Pbo

Keller, 2001

275 Paroxetine 66 48

Imipramine 52 48

Braconnier, 2003

121 Paroxetine 65 --

Clomipramine 48 --

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

0.5

1

1.5

2

2.5

3

Baseline Endpoint

ParoxetineImipraminePlacebo

p = .001

Keller et al., 2001 Keller, M et al (2001). J Am Acad Child Adolesc Psychiatry, 40(7), 762-772.

Hamilton Depression - 17 Item Scores

0

4

8

12

16

20

ParoxetineImipraminePlacebop = .13

Sertraline in Juvenile DepressionWagner, 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)

-35

-30

-25

-20

-15

-10

-5

0Baseline Wk 1 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10

SertralinePlacebo

p < .05

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., 2001Wagner, K. (2001). Presented at the Annual Meeting of the College of Neuropsychopharmacology,

San Juan, Puerto Rico.

Child Depression Rating Scale (> 40)

-25

-20

-15

-10

-5

0Baseline Wk 1 Wk 2 Wk 4 Wk 6 Wk 8

CitalopramPlacebop < .05

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 StudiesNefazodone

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

0

10

20

30

40

50

60

70

Wk 1 Wk 8

NFZPBO

p=.055

Controlled Juvenile StudiesMirtazapine

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

0

10

20

30

40

50

60

70

Wk 1 Wk 8

MTZPBO

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 depression63% Pts much improved ADHDSide 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

TADSTreatments for Adolescents With

Depression StudyPI: John S. March, MD, MPHPI: John S. March, MD, MPH

March J et al (2003). J Am Acad Child Adolesc Psychiatry, 42:531-541.

To examine the effectiveness, including cost effectiveness, of medication (fluoxetine) and cognitive-behavioral psychotherapy, alone and in combination, for the acute and long-term treatment of adolescents with DSM-IV Major Depression

Purpose of TADS

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 supportCBT +/- 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 maternal-

child warmth, parental-child tension, impaired peer relationships

(Geller et al., 2001)

Prepubertal & Early Adolescent Bipolar Disorder

Type of Cycles PrepubertalN=53

PubertalN=40

Rapid(4 cycles/yr)

0 0

Ultrarapid(5-364 cycles/yr)

4% (2/53) 18% (7/40)

Ultridian(>364 cycles/yr)

81% (43/53) 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

0

1626

56

15

37

48

88

0102030405060708090

Psychosis Mult Anx Conduct ODD

ADHD Bipolar

Wozniak, J. data presented at MGH ADHD Course March 7-9, 2003 Boston, MA

Per

cen

t

0

5

10

15

20

25

30

% o

f g

rou

p

Baseline Year 1 Year 4

ADHD Control

p<0.01

p<0.01

p<0.01

ADHD and BPD: Results from 4-Year Follow-Up Study

Overall rate of Bipolar Disorder

Biederman J, et al. Arch Gen Psychiatry 53:437-46, 1996

Improvement of ADHD Before and After Improvement of Manic Symptoms

0

5

10

15

20

25

% o

f vi

sits

im

pro

ved

Before After

Odds Ratio = 7.5 (1.1-52.2) p<0.04

The probability of ADHD improvement was 7.5 times higher following initial improvement in manic symptoms

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

1

2

3

4

5

6

7 Pre-treatment

Post-treatment

Mild

Moderate

Severe

(N=28) (N=25) (N=13) (N=28)

p<.01

MEAN CGI SEVERITY (N = 28)

Mania ADHD Psychosis Aggression

p<.01p<.001

(Frazier et al., 1998)

There was a significant improvement in Young Mania Rating Scale Total scores from baseline to endpoint following olanzapine treatment.

Open Trial of Olanzapine in Juvenile BPD (Frazier et al., JCAP 2001)

-19.04-20

-10

0Baseline:

******p < .001

Mea

n C

han

ge

to E

nd

po

int

-5

-15

Young Mania Rating Scale30.70

Children’s Depression Rating Scale44.57

-14.22 ***

0 1 2 3 4 5 6 7 8

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Week, Post-Baseline

p<0.001

CGI-BP Severity of Overall

Illness Scale: Weekly Change

from Baseline (LOCF)

Weight Gain (Kg)

Weekly Change From Baseline

(LOCF)

Olanzapine in Pediatric Bipolar Disorder:Open Label, 8 - Weeks, n=23

Frazier et al, JCAP, 2001

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 1st-line treatment, alone or with Mood Stabilizers

Awaiting controlled data to compare specific agents for efficacy and side effect differences