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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.