1. Depression in Children and Adolescents Graham J. Emslie, M.D. UT Southwestern Medical Center at Dallas and Children’s Medical Center

2. Black Box Warning Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Drug Name] or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. [Drug Name] is not approved for use in pediatric patients…. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

3. PUBLISHED TRIALS StudyNAgesCGI-I (1 or 2) p Fluoxetine (1997) 967-17 56% vs. 33%.02 Fluoxetine (2002) 2198-17 52% vs. 37%.028 Paroxetine (2001) 27512-18 66% vs. 48%.02 Sertraline (2003) 3766-17 63% vs. 53%.05 Citalopram (2004) 1747-17 47% vs. 45% NS

4. NUMBER OF SITES AND RESPONSE RATE DIFFERENCES # of Sites # Subjects per Site Placebo Response Fluoxetine (1997) 19623% Paroxetine (2001) 10≈2817.3% Fluoxetine (2002) 15≈1516.5% Sertraline (2003) 53≈710% Citalopram (2004) 21≈82% *Based on CGI-Improvement of 1 or 2.

5. OTHER SSRI TRIALS StudyNAgesCGI-I (1 or 2) p Paroxetine #377 (AACAP, 1999) 27513-18 69% vs. 57% NS Paroxetine #701 (AACAP, 2004) 2037-17 49%vs. 46%.563 Escitalopram (AACAP, 2004) 1646-17 63%vs. 53% NS Citalopram (MHRA report) 23313-18UNKUNK

6. NSRI TRIALS StudyNAgesCGI-I (1 or 2) p Nefazodone (APA, 2002) 19512-17 65% vs. 46%.005 NefazodoneUNK7-17UNKNS Mirtazapine1267-17 59.8% vs. 56.8% NS Mirtazapine1327-17 53.7% vs. 41.5% NS Venlafaxine (APA, 2004) #3821617-17 50% vs. 41%.314 Venlafaxine (APA, 2004) #394 1937-17 67% vs. 61%.370

7. SUICIDAL BEHAVIOR

8. Suicidal Behavior  General population:  9% of teens make an actual suicide attempt.  19% of teens have suicidal ideation.  Suicidal behavior is a symptom of depression.  35-50% of depressed teens make a suicide attempt.  Suicide rates have decreased over the past decade, as antidepressant prescriptions have increased.  6 completed suicides per 100,000 (.006%) ** Olfson et al. 2003; World Health Organization 2003

9. What is the Classification Scheme? SuicidalNon Suicidal Suicide Attempt Code= 1 N= 36 Suicidal Ideation Code=6 N=62 Self-Injurious Behavior Without Suicidal Intent Codes=4,5,,11 N=17 Other: -Accidental -Psychiatric -Medical Codes=7,8,9,12 N= 260 Indeterminate Non- Consensus N = 0 Not Enough Information: Unable to Classify Whether Deliberate Self- Injury or “other” Code = 10 N = 9 Preparatory Actions Towards Imminent Suicidal Behavior Code =2 N = 8 Self-Injurious Behavior With Unknown Intent Code=3 N=35 ? Suicidal * From Columbia University

10. Fixed Effect Results on Suicidal Behavior/Ideation (1,2,6) and on Possible Suicidal Behavior/Ideation (1,2,3,6,10) For All Trials and SSRI/MDD Trials (23 drug program trials + TADS) Trial Group RR (95% CI) for 1,2,6 (Suicidal Behavior/Ideation) RR (95% CI) for 1,2,3,6,10 (Possible Suicidal Behavior/Ideation) All Trials & Indications (23 + 1) 1.95 (1.28,2.98)* 2.19 (1.50,3.19)* SSRI/MDD Trials (10 + 1) 1.66 (1.02,2.68)* 1.91 (1.27,2.89)*

11. Fixed Effect Results on Suicidal Behavior/Ideation (1,2,6), Suicidal Behavior (1,2), and Suicidal Ideation (6) By Drug in MDD Trials (Seven Programs) Drug Program (# of trials) RR (95% CI) for 1,2,6 (Sui Behav/Ideation) RR (95% CI) for 1,2 (Sui Behav) RR (95% CI) for 6 for 6 (Sui Ideation) Celexa (2) 1.37 (0.53,3.50) 2.23 (0.59,8.46) 0.75 (0.19,2.95) Effexor (2) 8.84 (1.12,69.51)* 2.77 (0.11,67.10) 7.89 (0.99,62.59) Paxil (3) 2.15 (0.71,6.52) 2.30 (0.67,7.93) 1.09 (0.24,5.01) Prozac (3 + 1) 1.53 (0.74,3.16) 2.15 (0.50,9.26) 1.30 (0.59,2.87) Remeron (1) 1.58 (0.06,38.37) No Events 1.58 (0.06,38.37) Serzone (2) No Events Zoloft (2) 2.16 (0.48,9.62) 0.98 (0.17,5.68) 3.88 (0.44,34.54)

12. 95 cases of definitive suicidal behavior in 4,250 youth studied.

13. NO completed suicides in more than 2,800 depressed children and adolescents studied.

14. TOXICOLOGY STUDIES  80% of adults depressed patients were not on antidepressants at the time of the suicide  Gray et al., 2003  49 adolescent suicides  24% had been prescribed antidepressants  None tested positive for antidepressants  Leon et al., 2004  Post mortem study of 66 suicides in youth  54 (82%) had serum toxicology for antidepressants within 3 days of death  2 had imipramine and 2 had fluoxetine detected.

15. Alternative Treatments

16. Psychotherapies with Empirical Support Cognitive Behavioral Therapy (CBT) Cognitive Behavioral Therapy (CBT) –For children (Stark et al., 1987, 1991) Interpersonal Therapy (IPT) Interpersonal Therapy (IPT) –For adolescents (Mufson et al., 1999; Rossello and Bernal, 1999) CBT for adolescents CBT for adolescents

17. 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

18. TADS Design  439 Adolescents (12-17) with MDD  COMB: 107  FLX: 109  CBT: 111  PBO: 112  Acute treatment for 12 weeks  Independent Evaluations at Weeks 6 and 12

19. CDRS: Adjusted Means (ITT) T A D S

20. Suicidality Improves Overall (OC)

21. 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)

22. TASA Columbia Suicide History form to assess history of suicidal behaviors Columbia Suicide History form to assess history of suicidal behaviors SMURF to provide systematic assessment of all AEs. SMURF to provide systematic assessment of all AEs. SSRS to prospectively assess suicidal behavior at each visit. SSRS to prospectively assess suicidal behavior at each visit. Prodromal Symptoms form to assess other behavioral changes Prodromal Symptoms form to assess other behavioral changes

23. Conclusions 1. Depression is a serious disorder in children and adolescents. 2. Some studies indicate SSRIs are effective. 3. There is increased risk (4% vs. 2%) of suicidal behavior in youth treated with an antidepressant. 4. Suicidal thinking improves as depression improves. 5. One study demonstrated medication and medication plus therapy are effective, but therapy alone is not. Additional studies are needed.