Depression in Children Depression in Children and Adolescentsand Adolescents

Graham J. Emslie, M.D.Graham J. Emslie, M.D.UT Southwestern Medical Center at UT Southwestern Medical Center at Dallas and Children’s Medical CenterDallas and Children’s Medical Center

Black Box WarningBlack Box WarningAntidepressants increased the risk of suicidal thinking and Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Drug psychiatric disorders. Anyone considering the use of [Drug Name] or any other antidepressant in a child or adolescent Name] or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for Families and caregivers should be advised of the need for close observation and communication with the prescriber. close observation and communication with the prescriber. [Drug Name] is not approved for use in pediatric patients….[Drug Name] is not approved for use in pediatric patients….

The average risk of such events in patients receiving The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.suicides occurred in these trials.

PUBLISHED TRIALSPUBLISHED TRIALS

StudyStudy NN AgesAges CGI-ICGI-I

(1 or 2)(1 or 2)pp

Fluoxetine Fluoxetine (1997)(1997)

9696 7-177-17 56% vs. 56% vs. 33%33%

.02.02

Fluoxetine Fluoxetine (2002)(2002)

219219 8-178-17 52% vs. 52% vs. 37% 37%

.02.0288

Paroxetine Paroxetine (2001)(2001)

275275 12-1812-18 66% vs. 66% vs. 48%48%

.02.02

Sertraline Sertraline (2003)(2003)

376376 6-176-17 63% vs. 63% vs. 53%53%

.05.05

Citalopram Citalopram (2004)(2004)

174174 7-177-17 47% vs. 47% vs. 45%45%

NSNS

NUMBER OF SITES ANDNUMBER OF SITES ANDRESPONSE RATE RESPONSE RATE

DIFFERENCESDIFFERENCES# of # of

SitesSites# Subjects # Subjects

per Siteper SitePlacebo Placebo

ResponseResponse

Fluoxetine (1997)Fluoxetine (1997) 11 9696 23%23%

Paroxetine (2001)Paroxetine (2001) 1010 ≈≈2828 17.3%17.3%

Fluoxetine (2002)Fluoxetine (2002) 1515 ≈≈1515 16.5%16.5%

Sertraline (2003)Sertraline (2003) 5353 ≈≈77 10%10%

Citalopram (2004)Citalopram (2004) 2121 ≈≈88 2%2%

*Based on CGI-Improvement of 1 or 2.*Based on CGI-Improvement of 1 or 2.

OTHER SSRI TRIALSOTHER SSRI TRIALS

StudyStudy NN AgesAges CGI-ICGI-I

(1 or 2)(1 or 2)pp

Paroxetine #377Paroxetine #377

(AACAP, 1999)(AACAP, 1999)275275 13-1813-18 69% vs. 69% vs.

57%57%NSNS

Paroxetine #701Paroxetine #701

(AACAP, 2004)(AACAP, 2004)203203 7-177-17 49%vs. 49%vs.

46%46%.563.563

EscitalopramEscitalopram

(AACAP, 2004)(AACAP, 2004)164164 6-176-17 63%vs. 63%vs.

53%53%NSNS

Citalopram Citalopram (MHRA report)(MHRA report)

233233 13-1813-18 UNKUNK UNKUNK

NSRI TRIALSNSRI TRIALSStudyStudy NN AgesAges CGI-ICGI-I

(1 or 2)(1 or 2)pp

Nefazodone (APA, Nefazodone (APA, 2002)2002)

195195 12-1712-17 65% vs. 46%65% vs. 46% .005.005

NefazodoneNefazodone UNKUNK 7-177-17 UNKUNK NSNS

MirtazapineMirtazapine 126126 7-177-17 59.8% vs. 59.8% vs. 56.8%56.8%

NSNS

MirtazapineMirtazapine 132132 7-177-17 53.7% vs. 53.7% vs. 41.5%41.5%

NSNS

Venlafaxine (APA, Venlafaxine (APA, 2004)2004)

#382#382

161161 7-177-17 50% vs. 41%50% vs. 41% .314.314

Venlafaxine (APA, Venlafaxine (APA, 2004) #3942004) #394

193193 7-177-17 67% vs. 61%67% vs. 61% .370.370

SUICIDAL BEHAVIORSUICIDAL BEHAVIOR

Suicidal BehaviorSuicidal Behavior General population:General population:

9% of teens make an actual suicide 9% of teens make an actual suicide attempt.attempt.

19% of teens have suicidal ideation.19% of teens have suicidal ideation. Suicidal behavior is a symptom of Suicidal behavior is a symptom of

depression.depression. 35-50% of depressed teens make a suicide 35-50% of depressed teens make a suicide

attempt.attempt. Suicide rates have decreased over the past Suicide rates have decreased over the past

decade, as antidepressant prescriptions decade, as antidepressant prescriptions have increased.have increased.

6 completed suicides per 100,000 (.006%)6 completed suicides per 100,000 (.006%)** Olfson et al. 2003; World Health Organization 2003** Olfson et al. 2003; World Health Organization 2003

What is the What is the Classification Scheme?Classification Scheme?

Suicidal Non Suicidal

Suicide AttemptCode= 1N= 36

Suicidal IdeationCode=6N=62

Self-InjuriousBehaviorWithout SuicidalIntent Codes=4,5,,11N=17

Other:-Accidental-Psychiatric-MedicalCodes=7,8,9,12N= 260

Indeterminate

Non-ConsensusN = 0

Not Enough Information:Unable to Classify Whether Deliberate Self-

Injury or “other” Code = 10N = 9

Preparatory Actions Towards Imminent Suicidal BehaviorCode =2N = 8

Self-Injurious Behavior

With Unknown

IntentCode=3N=35

? Suicidal

* From Columbia University

Fixed Effect Results on Suicidal Behavior/Ideation Fixed Effect Results on Suicidal Behavior/Ideation (1,2,6) and on Possible Suicidal Behavior/Ideation (1,2,6) and on Possible Suicidal Behavior/Ideation

(1,2,3,6,10)(1,2,3,6,10)For All Trials and SSRI/MDD TrialsFor All Trials and SSRI/MDD Trials(23 drug program trials + TADS)(23 drug program trials + TADS)

Trial GroupTrial Group RR (95% CI) for RR (95% CI) for 1,2,61,2,6(Suicidal (Suicidal Behavior/Ideation)Behavior/Ideation)

RR (95% CI) for RR (95% CI) for 1,2,3,6,101,2,3,6,10(Possible Suicidal (Possible Suicidal Behavior/Ideation)Behavior/Ideation)

All Trials & All Trials & IndicationsIndications(23 + 1) (23 + 1)

1.95 1.95 (1.28,2.98)*(1.28,2.98)*

2.19 2.19 (1.50,3.19)*(1.50,3.19)*

SSRI/MDD TrialsSSRI/MDD Trials(10 + 1)(10 + 1) 1.66 1.66

(1.02,2.68)*(1.02,2.68)*1.91 1.91 (1.27,2.89)*(1.27,2.89)*

Fixed Effect Results on Suicidal Behavior/Ideation (1,2,6), Suicidal Fixed Effect Results on Suicidal Behavior/Ideation (1,2,6), Suicidal Behavior (1,2), and Suicidal Ideation (6)Behavior (1,2), and Suicidal Ideation (6)

By Drug in MDD Trials (Seven Programs)By Drug in MDD Trials (Seven Programs)

Drug ProgramDrug Program(# of trials)(# of trials)

RR (95% CI)RR (95% CI)for 1,2,6for 1,2,6

(Sui Behav/Ideation)(Sui Behav/Ideation)

RR (95% CI)RR (95% CI)for 1,2for 1,2

(Sui Behav)(Sui Behav)

RR (95% CI)RR (95% CI) for 6for 6

(Sui Ideation)(Sui Ideation)

Celexa (2)Celexa (2) 1.37 (0.53,3.50)1.37 (0.53,3.50) 2.23 (0.59,8.46)2.23 (0.59,8.46) 0.75 0.75 (0.19,2.95)(0.19,2.95)

Effexor (2)Effexor (2) 8.84 (1.12,69.51)*8.84 (1.12,69.51)* 2.77 2.77 (0.11,67.10)(0.11,67.10)

7.89 7.89 (0.99,62.59)(0.99,62.59)

Paxil (3)Paxil (3) 2.15 (0.71,6.52)2.15 (0.71,6.52) 2.30 (0.67,7.93)2.30 (0.67,7.93) 1.09 1.09 (0.24,5.01)(0.24,5.01)

Prozac (3 + 1)Prozac (3 + 1) 1.53 (0.74,3.16)1.53 (0.74,3.16) 2.15 (0.50,9.26)2.15 (0.50,9.26) 1.30 1.30 (0.59,2.87)(0.59,2.87)

Remeron (1)Remeron (1) 1.58 (0.06,38.37)1.58 (0.06,38.37) No EventsNo Events 1.58 1.58 (0.06,38.37)(0.06,38.37)

Serzone (2)Serzone (2) No EventsNo Events No EventsNo Events No EventsNo Events

Zoloft (2)Zoloft (2) 2.16 (0.48,9.62)2.16 (0.48,9.62) 0.98 (0.17,5.68)0.98 (0.17,5.68) 3.88 3.88 (0.44,34.54)(0.44,34.54)

95 cases of definitive 95 cases of definitive suicidal behavior in suicidal behavior in

4,250 youth studied.4,250 youth studied.

NONO completed suicides completed suicides in more than 2,800 in more than 2,800

depressed children and depressed children and adolescents studied.adolescents studied.

TOXICOLOGY STUDIESTOXICOLOGY STUDIES

80% of adults depressed patients were 80% of adults depressed patients were not on antidepressants at the time of the not on antidepressants at the time of the suicidesuicide

Gray et al., 2003Gray et al., 2003 49 adolescent suicides49 adolescent suicides 24% had been prescribed antidepressants24% had been prescribed antidepressants None tested positive for antidepressantsNone tested positive for antidepressants

Leon et al., 2004Leon et al., 2004 Post mortem study of 66 suicides in youthPost mortem study of 66 suicides in youth 54 (82%) had serum toxicology for 54 (82%) had serum toxicology for

antidepressants within 3 days of deathantidepressants within 3 days of death 2 had imipramine and 2 had fluoxetine 2 had imipramine and 2 had fluoxetine

detected.detected.

Alternative Alternative TreatmentsTreatments

Psychotherapies with Psychotherapies with Empirical SupportEmpirical Support

Cognitive Behavioral Therapy (CBT)Cognitive Behavioral Therapy (CBT)– For children (Stark et al., 1987, 1991)For children (Stark et al., 1987, 1991)

Interpersonal Therapy (IPT)Interpersonal Therapy (IPT)– For adolescents (Mufson et al., 1999; For adolescents (Mufson et al., 1999;

Rossello and Bernal, 1999)Rossello and Bernal, 1999)

CBT for adolescentsCBT for adolescents

Anne Marie Albano: NYU

Bruce Waslick: Columbia

Elizabeth Weller: Penn

Graham Emslie: UT Southwestern

Chris Kratochvil: Nebraska

Mark Reineke: U Chicago / Northwestern

David Rosenberg: Wayne State

Charles Casat: Carolinas Med Ctr

John Walkup: Hopkins

Paul Rohde / Anne Simmons: U Oregon

Norah Feeney: Case Western

Sanjeev Pathak: Cincinnati

TADS DesignTADS Design

439 Adolescents (12-17) with MDD439 Adolescents (12-17) with MDD COMB: 107COMB: 107 FLX: 109FLX: 109 CBT: 111CBT: 111 PBO: 112PBO: 112

Acute treatment for 12 weeksAcute treatment for 12 weeks Independent Evaluations at Weeks Independent Evaluations at Weeks

6 and 126 and 12

CDRS: Adjusted Means (ITT)

30

40

50

60

Baseline Week 6 Week 12

Stage I Assessments

Me

an

CD

RS

Sc

ore

- A

dju

ste

d

COMB

FLX

CBT

PBO

T A D S

Suicidality Improves Overall (OC)

21.4

29.2

7.8

13.3

6.6

9.6

0

5

10

15

20

25

30

Pe

rce

nt

Baseline Week 6 Week 12

CDRS13 >2SIQ >= 31

• Columbia University (Larry Greenhill, MD)

• NYU (Barbara Coffey, MD)

• University of Pittsburgh (Oscar Bukstein, MD)

• Duke University (Karen Wells, PhD)

• Johns Hopkins (John Walkup, MD)

• UT Southwestern (Graham Emslie, MD)

• NIMH (Ben Vitiello, Joanne Severe, Ann

Wagner)

Treatment of Adolescent Suicide Attempters (TASA)

TASATASA

Columbia Suicide HistoryColumbia Suicide History form to form to assess history of suicidal behaviorsassess history of suicidal behaviors

SMURFSMURF to provide systematic to provide systematic assessment of all AEs.assessment of all AEs.

SSRSSSRS to prospectively assess to prospectively assess suicidal behavior at each visit.suicidal behavior at each visit.

Prodromal SymptomsProdromal Symptoms form to form to assess other behavioral changesassess other behavioral changes

ConclusionsConclusions

1.1. Depression is a serious disorder in Depression is a serious disorder in children and adolescents.children and adolescents.

2.2. Some studies indicate SSRIs are Some studies indicate SSRIs are effective.effective.

3.3. There is increased risk (4% vs. 2%) of There is increased risk (4% vs. 2%) of suicidal behavior in youth treated with suicidal behavior in youth treated with an antidepressant.an antidepressant.

4.4. Suicidal thinking improves as Suicidal thinking improves as depression improves. depression improves.

5.5. One study demonstrated medication One study demonstrated medication and medication plus therapy are and medication plus therapy are effective, but therapy alone is not. effective, but therapy alone is not. Additional studies are needed.Additional studies are needed.