1. Copyright © The REACH Institute. All rights reserved. It is the policy of the University of Arkansas for Medical Sciences (UAMS) College of Medicine to ensure balance, independence, objectivity, and scientific rigor in all provided or jointly provided educational activities. All individuals who are in a position to control the content of the educational activity (course/activity directors, planning committee members, staff, teachers, or authors of CME) must disclose all relevant financial relationships they have with any commercial interest(s) as well as the nature of the relationship. Financial relationships of the individual’s spouse or partner must also be disclosed, if the nature of the relationship could influence the objectivity of the individual in a position to control the content of the CME. The ACCME describes relevant financial relationships as those in any amount occurring within the past 12 months that create a conflict of interest. Individuals who refuse to disclose will be disqualified from participation in the development, management, presentation, or evaluation of the CME activity. UAMS Disclosure Policy

2. Copyright © The REACH Institute. All rights reserved. Disclosures The following planners and speaker of this CME activity has no relevant financial relationships with commercial interests to disclose: Lawrence Amsel, M.D. Suzanne Reiss, M.D. Diane Bloomfield, M.D. Mark Riddle, M.D. Cathryn Galanter, M.D. Jyoti Bhagia, M.D. Harlan Gephart, M.D. Ruth Stein, M.D. Peter Jensen, M.D. Mark Wolraich, M.D. Robert Kowatch, M.D. Rachel Zuckerbrot, M.D. Rachel Lynch, M.D. Elena Man, M.D.

3. Copyright © The REACH Institute. All rights reserved. Disclosures The following planner and speaker of this CME activity has financial relationships with commercial interests to disclose: Laurence Greenhill, M.D. –Bio BDX – Scientific Advisory Board

4. Copyright © The REACH Institute. All rights reserved. Understanding the FDA Boxed Warning

5. Copyright © The REACH Institute. All rights reserved. Hidden Slide: Time Table Total time: 25 minutes Intro/Goals and Objectives: 2’ Safety and efficacy of antidepressant use in children and adolescents: 14’ Discuss clinical recommendations for the use of antidepressant use in children and adolescents: 7’ Summary/wrap up: 2’ Point out handouts at back of section:  SSRI letter for parents  Assessing suicide risk for providers  Suicide prevention for parents 5 Unit F: Understanding the FDA Boxed Warning

6. Copyright © The REACH Institute. All rights reserved. Learning Objectives Review the data that led to the FDA’s Boxed Warning for SSRIs Describe safety and efficacy considerations of antidepressant use in children and adolescents Explain clinical recommendations for the use of antidepressant use in children and adolescents

7. Copyright © The REACH Institute. All rights reserved. HIDDEN SLIDE No more Black Box Warning http://healthjournalism.org/blog/2009/07/fda- rethinks-black-box-warning/http://healthjournalism.org/blog/2009/07/fda- rethinks-black-box-warning/ FDA official wants media to stop using term ‘Black Box’ & just say ‘Boxed Warning.’ ‘Black Box carries implication ‘Don’t you dare use this.”” Decision has to be made with family about the risk and benefit in using the drugs, and monitoring the patients closely

8. Copyright © The REACH Institute. All rights reserved. RESOURCE SLIDE: In the News… Aug 2003 Aug 2003 Wyeth: “…increased reports…of hostility and suicide-related adverse events.” Oct 2003 Oct 2003 FDA: “…data suggest an excess of (suicidality) reports”; plan for investigation of 8 antidepressants British MHRA: “The majority of SSRIs… are not suitable to be used by under 18’s.” “Risks…outweigh benefits….” Dec 2003 Dec 2003 ACNP: “…several SSRI trials show efficacy…”; “…no statistically significant increases in suicidal behavior…” Jan 2004 Jan 2004 Sep 2004 Sep 2004 Feb 2004 Feb 2004 FDA: Plan for reclassification of each suicidal event. FDA: Warnings to be placed on all antidepressants. “Black-box” warning

9. Copyright © The REACH Institute. All rights reserved. HIDDEN SLIDE The next slide will deal with risk-benefit analysis. Utilize a child with a sore throat who comes into the office and has positive, rapid strep. Walk providers through analysis of giving IM PCN versus a prescription for oral antibiotics. 9Unit F: Black Box Warning

10. Copyright © The REACH Institute. All rights reserved. How to Decide When to Use Any Medicine? Determine risks Determine benefits Assess risk-benefit ratio Discuss risk-benefit relationship with patient and caregivers Monitor for adverse events –Known and unknown

11. Copyright © The REACH Institute. All rights reserved. Benefits What “benefits” data did the FDA have at the time of the initial boxed warning? What “benefits” data has since emerged?

12. Copyright © The REACH Institute. All rights reserved. Pediatric Antidepressant Uses Mood Disorders –Major Depressive Disorder –Persistent Depressive Disorder –Bipolar Disorder –Other Anxiety Disorders –Generalized Anxiety Disorder –Obsessive Compulsive Disorder –Other Other second-line use –Attention Deficit Hyperactivity Disorder –Other (TCAs for enuresis, etc.)

13. Copyright © The REACH Institute. All rights reserved. Efficacy Data: Major Depressive Disorder Fluoxetine receives FDA approval for child and adolescent depression in January 2003 after two positive randomized controlled trials Many negative studies were unpublished NIMH-funded study, treatment for adolescents with depression study (TADS): large multi-site trial on adolescent depression becomes available (2004) and is our best gauge on efficacy

14. Copyright ©2014 The REACH Institute. All rights reserved. Children’s Depression Rating Scale: T A D S entry response

15. Copyright © The REACH Institute. All rights reserved. Efficacy Data: Major Depressive Disorder After the FDA review: –Escitalopram Studies (Wagner et al. 2006, Emslie et al 2009) –TORDIA Study (Brent et al. 2008) –Escitalopram receives FDA approval for MDD in 12 and up (2009)

16. Copyright © The REACH Institute. All rights reserved. Efficacy Data: Anxiety Disorders FDA approved fluoxetine, fluvoxamine, and sertraline for OCD in children and adolescents (prior to January 2003) RUPP Fluvoxamine (Luvox) study (2001) -> NEJM –fluvoxamine >> plb in SAD: SocialAnxietyDisorder, GAD: Generalized Anxiety Disorder, SPh: Social Phobia Pittsburgh Anxiety Study - Birmaher et al. (2003) -> JAACAP –fluoxetine > plb in SAD/GAD/SPh Brawman-Mintzer et al. (2006) –Sertraline >(tiny difference) PBO in GAD

17. Copyright © The REACH Institute. All rights reserved. Efficacy Data: Anxiety Disorders After the FDA Review: –CAMS study (Walkup et al., 2008)

18. Copyright © The REACH Institute. All rights reserved. Risks What was known about safety and risks at the time of the FDA review? What has been learned since?

19. Copyright © The REACH Institute. All rights reserved. FDA Pooled Analyses Data pooled from 24 studies –Pharmaceutical data (23 total studies) 15 for MDD 8 for other mental health disorders (obsessive- compulsive disorder, anxiety, ADHD) –TADS (Treatment of Adolescent Depression) study

20. Copyright © The REACH Institute. All rights reserved. What Were Limitations of the Data? Majority of pharmaceutical studies were voluntarily done to obtain exclusivity Studies had small samples and were inadequately powered to detect a rare event like suicidality Studies were of short duration (<16 weeks) Studies had selection bias due to variations in sample inclusion Less attention was paid to procedures Limited uniformity across the studies

21. Copyright © The REACH Institute. All rights reserved. Adverse Events: Data Problems FDA data was based on spontaneous reports, not a systematic suicide risk assessment done uniformly across studies Columbia University needed to reclassify these events, although available data had significant limitations: Feb 2004

22. Copyright © The REACH Institute. All rights reserved. Results: Pooled Data Safety –Relative risk of suicidality (thoughts or behaviors) is 2.19 X greater for drug compared to placebo (95% CI 1.5-3.19); p-value=.00005 –Conclusion: Suicidality in these children did not occur by chance alone. There is a 2% risk in placebo and a 4% risk with medication: September 2004

23. Copyright © The REACH Institute. All rights reserved. Completed Suicide No completed suicides in ANY of the acute studies

24. Copyright © The REACH Institute. All rights reserved. Suicidality Improves Overall T A D S

25. Copyright ©2014 The REACH Institute. All rights reserved. Suicide Ideation Questionnaire: Adjusted Means T A D S 25Unit F: Black Box Warning

26. Copyright © The REACH Institute. All rights reserved. The Role of Narratives in the FDA Hearing Comparable to case reports (although missing data) NOT CAUSAL ! Understand stakeholders’ perspectives (Scientology, lawsuits, etc.) ***Many have said that the anecdotal reports significantly influenced the decision regarding the FDA’s boxed warning

27. Copyright © The REACH Institute. All rights reserved. 2004 Black Box Warning up to the age of 18 Warned of increased suicidality Called for weekly visits for 4 weeks, every other week visits for another 8 weeks, and then monthly visits

28. Copyright © The REACH Institute. All rights reserved. SSRIs and Suicide

29. Copyright © The REACH Institute. All rights reserved. FDA-Recommended Warning Box and Close Monitoring In May 2007, the FDA ordered that all antidepressant medications carry an expanded warning box with information re: increased risk of suicidal symptoms in young adults 18-24 years of age “Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies with major depressive disorder (MDD) and other psychiatric disorders. Short term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24, and there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. This risk must be balanced with the clinical need. Monitor patients 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.”

30. Copyright © The REACH Institute. All rights reserved. In the 2007 changes to the Warning Box, the FDA discontinued its previous specific recommendations that C&A starting an antidepressant be followed weekly x 4 weeks, then q.o. week x 4 weeks, etc. NOTE: The Warning Box applies not just to antidepressants, but to all drugs with similar mechanisms: e.g., atomoxetine (SNRI approved for ADHD) has a Warning Box. Suicidality may occur with medications without a Warning Box, i.e. even though stimulants are not officially “labeled” as linked to suicidality, they can cause emotionality/over-arousal that might in some vulnerable patients present as suicidality. FDA-Recommended Warning Box and Close Monitoring

31. Copyright © The REACH Institute. All rights reserved. The Risk-Benefit Ratio

32. Copyright © The REACH Institute. All rights reserved. Pros and Cons to the Warning Box Pros Encourages consideration of risks/benefits before prescribing Encourages partnerships with family Encourages exploration of all other available options May result in more appropriate monitoring of patients Cons Increased Fear: patients Increased Fear: parents Increased Fear: prescribers Seriously impaired children may go untreated Children may be treated inappropriately with alternative medications

33. Copyright © The REACH Institute. All rights reserved. Interpretation  SSRIs efficacious for depression, OCD, and non-OCD anxiety. Benefits of SSRIs much greater than risks for suicidality (Bridge et al., JAMA 2007:18,297:1683-96)  Antidepressants may slightly increase rates of suicidal “events” (thoughts, attempts). Given 2,000,000 events, this is an important public health problem  Antidepressants speed recovery and improve functional outcomes, esp. if combined with CBT  Antidepressants likely prevent death by suicide, probably via effective treatment of depression  Co-administered CBT may protect against suicidal events and assists in monitoring

34. Copyright © The REACH Institute. All rights reserved. Clinical Realities We need to help anxious and depressed children SSRIs play a key role in several clinical scenarios: –Partial response to psychotherapy –Lack of availability of resources –Improve speed of response –SSRIs are effective Both Fluoxetine & Escitalopram have several positive studies for MDD and have FDA approval Three SSRIs with FDA approval for OCD SSRI data favorable for other Anxiety Disorders A risk-benefit ratio for one child may be different for another

35. Copyright © The REACH Institute. All rights reserved. Now What?

36. Copyright © The REACH Institute. All rights reserved. Summary: Clinical Recommendations A careful assessment is critical Partner with caregivers: –Families and patients need to be fully informed about the risks and benefits of antidepressant treatment. –Antidepressants should be initiated at a low dose and titrated as indicated and tolerated

37. Copyright © The REACH Institute. All rights reserved. Always Monitor: Treatment-emergent suicidality / Form a Safety Plan with families (see F1.1-1.4) Sudden changes in mood or behaviour Compliance Adverse events Treatment emergent comorbidity

38. Copyright © The REACH Institute. All rights reserved. Hidden Slide Point out the handouts on suicide and SSRIs, suicide risk assessment, and safety planning Mention that at the end of Unit H, the depression treatment unit, they will split into pairs to get experience performing safety planning with families and patients and discussing SSRIs and the black box F 1.1- 1.4 38Unit F: Black Box Warning

39. Copyright © The REACH Institute. All rights reserved. REMINDER: REMINDER: Please fill out Unit F evaluation

40. Copyright ©2014 The REACH Institute. All rights reserved. NNT = 10 NNH = 112 RESOURCE SLIDE Putting It Together: SSRI Risk vs. Benefits Meta-Analysis, 27 Trials (published & unpublished) Bridge et al. (JAMA 2007;18,297:1683-96)