1. Handouts to send: MoodCheck, HCL-32 Props: Load Internet: Set up Google on HCL-32

2. President

3. Antidepressants & Kids: Suicide & the Risk/Benefit of Treatment Rick Bingham, MD Salem, OR 6/6/08

4. No Financial Conflicts of Interest

5. Outline Antidepressants are needed, valuable tools –Biology of antidepressant action –Untreated anxiety and depression is devastating –Antidepressants work Antidepressants & Suicide Risk –FDA –Subsequent research The Future –Research underway (including CAPTN) –Primary Care & Mental Health Collaboration Take Home –Prescribing antidepressants –Tools & Resources

6. Finding balance Do no harm Prevent secondary Make effective use of the tools we have

8. Antidepressant suicidality Risks of untreated depression ?

9. Antidepressants Treated Depression

10. Suicidality Antidepressants Treated Depression

11. Untreated depression: Recurrence School performance↓ Job failure Relationship failure Health consequences Suicidality Antidepressants Treated Depression

12. Untreated depression: Suicide Recurrence School performance↓ Job failure Relationship failure Health consequences Suicidality Suicide death Antidepressants Treated Depression

13. Untreated depression: Suicide Recurrence School performance↓ Job failure Relationship failure Health consequences Suicidality Suicide death Antidepressants Treated Depression Antidepressant Suicidality Depression Consequences

14. Untreated depression: Suicide Recurrence School performance↓ Job failure Relationship failure Health consequences Suicidality Suicide death Antidepressants Treated Depression Antidepressant Suicidality Depression Consequences

15. Confound and Confusion

16. Other issues- make visual Corporate Greed (E Spitzer law suit GlaxoSmith Kline Triumph of public health over Big Pharma?

18. TIME 8/2002

21. Too hot to touch-visual

22. Psychiatry has other obstacles Something about the difference with psychiatry Continuing questions Continuing stigma and misunderstanding Affect of lay media (get visual = drugging kids) Concerns about developing brain

24. Carving Nature at it’s Joints

25. DSM at ~400 diagnoses: Carving Nature at its Feathers?!

26. Medications risk to brain development- visual

27. Suicide 101 In rank order, a common cause of death Almost all have psychiatric disorders The majority have a mood disorder The majority are not in treatment A very small fraction are on antidepressants at the time of death by suicide (3%)

29. Psychiatrically Ill Deaths Mood Disorders Suicide 101 On Antidepressants

30. Antidepressant suicidality Risks of untreated depression ?

31. Pooled analysis, short-term placebo controlled Total of 24 trials Nine antidepressants 4400 patients MDD, OCD, anxiety October 15, 2004

32. Suicidal thinking and behavior increased on antidepressants No suicide deaths occurred Absolute Risk on Placebo= 2% Absoulte Risk on Antidepressant= 4% Relative Risk Difference= 2% October 15, 2004

34. Antidepressants per 1000 medication users Suicides / 100,000 population 1990 2000 [You’ll have to comment about the scale, the small change, but relative to the other graphs we made, same ballpark and significant Olfson et al, Arch Gen Psych 2003

35. Gibbons et al, Am J Psych 2007 1988 1992 1996 2000 2004 Suicide rate per 100,000 2.5 3.0 3.5 4.0 4.5 U.S. Suicide Rates, <20 years old Warnings: UK Health Canada FDA

36. Decreasing Antidepressants (teens) Unchanged Suicide Rate Wheeler. BMJ 2008; 336: 542-

37. Katz et al, Can Med Assoc J, 2008 Canadian Suicide Rates, 8-17 year olds Warnings: UK Health Canada FDA

38. Black box changed some 19-24

39. What is the mechanism?

40. Do antidepressants work? If not, this is a “No brainer”

41. Efficacy of Antidepressants in Kids PlaceboAntidepressantDifference Depression50%61%11% OCD32%52%20% Non-OCD Anxiety 39%69%30% Bridge, J et. al. JAMA. 2007; 297:1683-1696

42. Efficacy of Fluoxetine in Kids PlaceboFluoxetineDifference Depression42%62%20% OCD28%51%23% Non-OCD Anxiety 35%61%26% Bridge, J et. al. JAMA. 2007; 297:1683-1696

43. Epidemiology Common Start early devestating Undertreated

44. Brain: a different organ

45. Risk vs. Benefit for Kids NNTNNH Non-OCD Anxiety3200 OCD6143 Depression10112 Bridge, J et. al. JAMA. 2007; 297:1683-1696

46. Compare to Asthma

47. LABA Parallel Example Two columns with checks for similarities and no checks for differences

48. Summarize the LABA story

49. Salpeter, S. R. et. al. Ann Intern Med 2006;144:904-912 Effect of long-acting {beta}-agonists compared with placebo on odds ratio of life- threatening asthma exacerbations

50. From “Suicidality” to Suicide Death Suicide Death NNH: 1/280,000 Suicidality NNH: 1/143 Suicide Attempt NNH: 1/280 Attempt / Death : 1 / 1000

51. Translating “Suicidality” to Suicide Death Suicidality or suicide attempt is a proxy for Suicide A rough proxy, since attempts are much less common ~1000 attempts for every suicide SO With “suicidality” NNH = 143 but only ~half were attempts, thus NNH ~ 280 Translating attempts to suicide deaths (x 1000) = 280,000 OR ~1 per one quarter million

52. Intracellular Tug-of-War Atrophic Factors: glutamate, cortisol Trophic Factors: BDNF, bcl-2 Courtesy Jim Phelps, MD

53. Neuroplasticity and Cellular Resilience BDNF anti- depressants PI-3 (inositol- lipid pathway) GSK-3 BAD GR Bcl-2 exercise (!) omega-3’s (fish oil) ? lithium CREB valproate Stress/ Depression glutamate calcium cortisol lamotrigine (?) Courtesy Jim Phelps, MD

54. Neuroplasticity and Cellular Resilience BDNF anti- depressants PI-3 (inositol- lipid pathway) GSK-3 BAD GR Bcl-2 exercise (!) omega-3’s (fish oil) ? lithium CREB valproate Stress/ Depression glutamate calcium cortisol lamotrigine (?) Courtesy Jim Phelps, MD

55. Take Home Messages Screen for bipolar disorder Collect family history Use antidepressants with appropriate monitoring Refer kids to evidence-based psychotherapy

56. Bipolar Disorder … patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. October 2004

57. "Health care providers should instruct patients, their families and their caregivers to be alert for the emergence of agitation, irritability, and the other symptoms described above, as well as the emergence of suicidality and worsening depression". Anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania have been reported…[w/ AD’s] March 22, 2004

58. SERT

59. Because antidepressants are believed to have the potential for inducing manic episodes in patients with bipolar disorder, there is a concern about using antidepressants alone in this population [bipolar]. Therefore, patients should be adequately screened to determine if they are at risk for bipolar disorder before initiating antidepressant treatment so that they can be appropriately monitored during treatment. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. March 22, 2004

60. GENERAL BEHAVIOR INVENTORY Mania-Parent Version (GBI-P-M)

62. Which antidepressants?

63. What to Monitor Worsening depression Agitation/Irritability Activation (speeded up movements & mind) Sleeplessness Intense anxiety

64. When to Monitor?

65. Thoughts about suicide or dying Attempts to commit suicide New or worse depression New or worse anxiety Feeling very agitated or restless Panic attacks Difficulty sleeping (insomnia) New or worse irritability Acting aggressive, being angry, or violent Acting on dangerous impulses An extreme increase in activity and talking Other unusual changes in behavior or mood

66. Thoughts about suicide or dying Attempts to commit suicide New or worse depression New or worse anxiety Feeling very agitated or restless Panic attacks Difficulty sleeping (insomnia) New or worse irritability Acting aggressive, being angry, or violent Acting on dangerous impulses An extreme increase in activity and talking Other unusual changes in behavior or mood

67. Combined Treatment of OCD: CBT + Sertraline54% CBT39% Sertraline21% Placebo 4% POTS Study (adolescent OCD): JAMA. 2004; 292:1969-1976

68. Combined Treatment of Depression: CBT + Fluoxetine71% CBT61% Fluoxetine43% Placebo 35% TADS Study (adolescent depression): JAMA. 2004; 292:807-820

69. Combined Treatment of OCD: CBT + Sertraline54% CBT39% Sertraline21% Placebo 4% POTS Study (adolescent OCD): JAMA. 2004; 292:1969-1976

70. Combined Treatment of Depression: CBT + Fluoxetine71% CBT61% Fluoxetine43% Placebo 35% TADS Study (adolescent depression): JAMA. 2004; 292:807-820

71. BMJ march 2008 1993 1997 2001 2005

72. Fluoxetine Associated with Birth of New Hippocampal Cells New neurons born in human hippocampus Study in mice –Fluoxetine known to show specific behavioral effects linked to its antidepressant effects –Focused x-rays blocked neurogenesis in hippocampus –With the the birth of new cells blocked, the behavioral/antidepressant effects of fluoxetine were rendered ineffective suggesting that this is the mechanism of action Science 2003 301: 805

74. Things like new or more intense suicidal thoughts, anxiety, agitation, irritability, or markedly increased physical or mental activity.

75. The Future Current Studies In Progress CAPTN Primary Care / Mental Health Collaboration –OOCAP / OPS Collaboration

76. CAPTN ASK WEEKLY ENROLLMENT (AS OF 5/30/08) ENROLLMENT GOAL 2,420 Site #Principal InvestigatorLocationTotal Enrolled AL520Nelson HandalDothan, AL28 IL226Phillip HeldingHinsdale, IL27 OH124Stephen GrcevichChagrin Falls, OH24 NC509Allan ChrismanDurham, NC16 OR701Rick BinghamSalem, OR15 SITES ENROLLING 41SUBJECTS ENROLLED 278

77. Hippocampus

78. Hippocampal Volume Loss Sheline et al Am J Psychiatry. 2003

79. Early-Onset Depression MacMaster and Kusumakar BioMedCentral (BMC) Medicine 2004 age: 13-18 years old illness duration: 2.89 yrs avg mean onset: 14 yrs old Left: 17% decrease vs. controls

80. Thanks: Jim Phelps, M.D. www.PsychEducation.org

82. Copyright ©2002 BMJ Publishing Group Ltd. BMJ 2002;325:947 The leading causes of years lived with disability, worldwide, 1990

83. Objectives 1.Learn a little about the current scientific framework of how antidepressants work. 2.Understand the importance of actively identifying and treating anxiety and depression in children and adolescents. 3.Know the current status of research on the negative and positive affect of antidepressants on suicidal thoughts, behavior, and suicide death. 4.Understand how primary care clinicians should rationally include antidepressants in the treatment of anxiety and depression in kids even in the context of concerns about suicide risk.