Juvenile Depression Jeff Q. Bostic, M.D., Ed.D. Massachusetts General Hospital Harvard Medical School

1. Juvenile Depression Jeff Q. Bostic, M.D., Ed.D. Massachusetts General Hospital Harvard Medical School

2. Disclosure Statement Relationship/Role Commercial Enterprise(s) Research Grant: Glaxo Wellcome Eli Lilly Forest Pfizer Smith-Kline Abbott Speaker’s Honoraria: Glaxo-Wellcome Forest

3. AACAP Policy Statement 2000 • Most psychoactive agents lack FDA approval • “In making decisions to prescribe such medications the physician…should: • Consider data from studies in adults in treating the target disorder • Any clinical or anecdotal reports of use in child and adolescent patients, • Studies conducted outside the United States • And the experience of colleagues.” (AACAP Council , 2000)

4. How Significant is Depression? Depression or Dysthymia =17% Most people in20’s,>50% by age 40 By adolescence ~8%,girls > boys2:1 Depression > all age groups Suicide quadrupled among youth since 1950 But leveled off in 1988, and began decreasing in 1994

5. Assessment of Mood Disorders • Internalizing Symptoms: Children (Mood, Guilt/Criticism, Anhedonia) • Externalizing Symptoms: Parents, Teachers (Withdrawal, Appetite, Sleep) • Rating Scales (Beck Depression Inventory, Children’s Depression Inventory: low specificity) • Biological Markers: None yet

6. Assessment of Suicidality • Explore with patient, family, friends, teachers • Inquire about previous thoughts and attempts • Identify “reasons for living” • Distinguish suicidality from self-mutilation • Determine access to means of suicide (remove weapons, particularly guns)

7. Bipolar “Switching” Predictors • Family History of Bipolar Disorder • Psychomotor Retardation rather than Agitation • Psychosis • Hypersomnia • Rapid Onset of Depression (Bowden & Rhodes, Psychiatric Annals, 26 suppl: 430-434, 1996)

8. Juvenile Mood DisordersBostic, 2003 3 Domains of Child Function Family Friends School

9. Indications for Antidepressants • Depression Impairs Multiple Domains • Recurrent Depressive Episodes • Unwilling to Undergo Psychotherapy • Depression + Psychosis • Bipolar Depression

10. Controlled TCA Trials:Children

11. Controlled TCA Trials:Adolescents

12. Controlled TCA Trials:Adolescents • Desipramine in Adolescents 2001 • Controlled Trial, 30 Pts, aged 13 –19 • Mexico City National Institute of Psychiatry • Dosing: 150mg/d for 10 wks • Ratings weekly with Beck and Depression Self Rating Scale • DMI: 57% responded • PBO: 54% responded • SE: DMI > PBO (p=0.015)

13. Cochrane Review of TCAs in Pediatric MDD • Thirteen RCTs involving 506 participants aged 6-18 years • No overall improvement with treatment compared to placebo • Small advantage for TCAs in adolescents, but not children • Treatment with a tricyclic caused more vertigo, orthostatic hypotension, tremor and dry mouth • CONCLUSION: TCAs are ineffective Hazell, P et al (2002). Tricyclic drugs for depression in children and adolescents. Cochrane Database Syst Rev(2), CD002317.

14. Juvenile Mood DisordersBostic, 2001 TCA’s in Juveniles • 6 DB, PC trials in children • 5-9% benefit over placebo • 7 DB, PC trials in adolescents • 8-14% benefit over placebo

15. Serotonin Reuptake Inhibitors (SRI’s) • Fluoxetine (Prozac) • Sertraline (Zoloft) • Paroxetine (Paxil) • Citalopram (Celexa);Escitalopram (Lexapro) • Fluvoxamine (Luvox)

16. Controlled Fluoxetine Trials: Juvenile MDD

17. Emslie et al., 97, 02 Emslie, G. et al. (1997). Archives of General Psychiatry, 54(11), 1031-1037. Emslie, G. et al. (2002). J Am Acad Child Adolesc Psychiatry, 41(10), 1205-1215. Decrease in CDRS (Baseline > 40)

18. SSRIs and Growth Suppression • 4 Pts (1 F), age 11-14, with OCD or Tourette’s • Fluoxetine 20-80mg/d or Fluvoxamine 50-100mg/d • Growth deceleration on SSRI, reversed off SSRI (Weintrob et al., Arch Pediatr Adolesc Med, 156:696, 2002)

19. Double-Blind Paroxetine Trials: Juvenile MDD

20. Paroxetine in Pts < 18 (Washington Post, 6-11-03) • Paroxetine (Seroxat; Paxil) “increase in rate of self-harm and potentially suicidal behavior in this age group” Medicines & Healthcare Products Regulatory Agency • 1385 pts in 9 studies: Juvenile MDD (n= 663; 8-12 wks, 10-50mg/d), OCD (n=400), Social Anxiety (n=322) • Treatment + Taper + 30-day followup • 33 showed signs of mood swings that included suicidal thinking and suicide attempts • 1.2% PBO (n=8) vs. 3.4% (n=25) in PRX Group

21. Keller et al., 2001 Keller, M. (2001). J Am Acad Child Adolesc Psychiatry, 40(7), 762-772. Hamilton Depressed Mood Score p = .001

22. Keller et al., 2001 Keller, M et al (2001). J Am Acad Child Adolesc Psychiatry, 40(7), 762-772. Hamilton Depression - 17 Item Scores p = .13

23. Sertraline in Juvenile Depression Wagner, K. (2002). Sertraline in Pediatric Major Depression. Paper presented at the Annual Meeting of the American Psychiatric Association, Philadelphia, Pennsylvania. • DB, PC Trial, 10 wks • 376 Pts: 177 aged 6-11; 199 aged 12-17 • 56 sites: US, Canada, Costa Rica, Mexico, Brazil • Dose: 102 mg/d kids, 133mg/d teens • Side Effects:Diarrhea (11%), Vomiting (9%), Anorexia (7%), Agitation (7%) • Discontinuation: 9% SRT v. 2% Pbo

24. Wagner et al., 2002 Wagner, K. (2002). Sertraline in Pediatric Major Depression. Paper presented at the Annual Meeting of the American Psychiatric Association, Philadelphia, Pennsylvania. Child Depression Rating Scale (> 40) p < .05

25. Citalopram in Juvenile Depression • Wagner et al., 2001 • DB, PC, 8 Weeks • 174 Pts: 83 aged 7-11; 91 aged 12-17 • Dose: 23mg/d children; 24mg/d adolescents • Side Effects: Nausea (14%); Rhinitis (14%) • Discontinuation: 5.9% (CIT) v. 5.6% (PBO)

26. Wagner et al., 2001 Wagner, K. (2001). Presented at the Annual Meeting of the College of Neuropsychopharmacology, San Juan, Puerto Rico. Child Depression Rating Scale (> 40) p < .05 p < .01

27. Juvenile Depression: Citalopram • Of those who responded to CIT, 71% had failed previous SSRI’s • 8/10 with comorbid depression and anxiety responded • Comorbid ADHD: • 6/7 with MDD + ADHD responded • 5/6 with Anxiety + ADHD responded Bostic et al (2001). J Child Adol Psychopharm, 11:159-166.

28. Atypical Antidepressants Venlafaxine (Effexor) Nefazodone (Serzone) Mirtazapine (Remeron) Bupropion (Wellbutrin)

29. Controlled Venlafaxine Trials: Juvenile MDDMandocki MW et al (1997). Psychopharm Bull, 33:149-154

30. Venlafaxine in Pts < 18 (Wyeth Prescribing Letter, 8-22-03) • (Effexor IR/XR) “In pediatric clinical trials, there were increased reports of hostility and, especially in Major Depressive Disorder, suicide-related adverse events such as suicidal ideation and self harm.” • In Pts (6-17) in GAD and MDD trials, no efficacy: • Hostility: 2% VFX XR v. < 1% PBO • Suicidal Ideation: 2% VFX XR v. 0% PBO • No actual suicides in these clinical trials

31. Controlled Juvenile Studies Nefazodone • 195 Pts with MDD (99 NFZ v. 96 Pbo) • Age: 12-17, treated 8 weeks • Dosing: 100-600mg (x=444mg/d) • Dropouts: 27% (Emslie et al., Presented at NCDEU, 2002)

32. Nefazodone p=.055

33. Controlled Juvenile Studies Mirtazapine • 250 Pts with MDD (165 MTZ v. 65 Pbo) • Age: 7-17, treated 8 weeks • Dosing: 15-45mg • Dropouts: 5% (Emslie et al., Presented at the 48th Annual AACAP Meeting, 2001)

34. Mirtazapine

35. Juvenile Depression: Bupropion SR (Wellbutrin; Zyban) • Open Trial of 10 weeks (+ 2wks SB Pbo) • 24 patients with ADHD + MDD or dysthymia • Dosing: 2.7mg/kg/am and 1.7mg/kg/pm Significant improvement by teacher & parent ratings Daviss B et al (2001). J Am Acad Child Adolesc Psychiatry, 40:307-314.

36. Juvenile Depression: Bupropion SR (Wellbutrin; Zyban) • 88% Pts much improved depression • 63% Pts much improved ADHD • Side effects < 10% except rash 13% which resolved while on BPN (nausea 13% during PBO run-in phase) Daviss B et al (2001). J Am Acad Child Adolesc Psychiatry, 40:307-314.

37. Maintenance Treatment • Remind Pt and Family of symptoms suggesting recurrence • See Pts every 2-4 months over next 8 months(Emslie et al., 1997) • If > 2 episodes, 95% chance recurrence (so continue Rx) • Taper other Rx first (e.g., neuroleptic)

38. Cognitive-Behavioral Therapy • 6 controlled trials in 165 juveniles • Efficacy: 62% vs. 36% (placebo) • Limitations: • Less benefit in children < 13 years old • Often reports with Group Sessions • Self-Report Measures • Dysphoria rather than MDD

39. TADS Treatments for Adolescents With Depression Study PI: John S. March, MD, MPH March J et al (2003). J Am Acad Child Adolesc Psychiatry, 42:531-541.

40. Purpose of TADS To examine the effectiveness, including cost effectiveness, of medication (fluoxetine) and cognitive-behavioral psychotherapy, alone and in combination, for the acute and long-term treatment of adolescents with DSM-IV Major Depression

41. Juvenile Depression: Summary • Depression may manifest differently in Juveniles • Consider Functional Impairment as Plan Treatment • Antidepressants: SRI’s have most support to date • CBT has support • CBT +/- Antidepressants being studied

43. Juvenile Bipolar Disorder Sandra DeJong, M.D., & Jeff Q. Bostic, M.D., Ed.D. Massachusetts General Hospital Harvard Medical School

44. Juvenile Bipolar Disorder • 93 Pts, aged 6-16 • Compared with 81 ADHD Pts, 94 controls • Symptomatically, BP Pts had: • Mixed mania: 55% Rapid Cycles: 87% • Psychosis: 60% Grandiose delusions: 50% • Suicidality: 25% • Recovery:15% by 6 months, 37% 1 yr, 56% 18 months • Functioning: More likely to have impaired maternal-child warmth, parental-child tension, impaired peer relationships (Geller et al., 2001)

45. Prepubertal & Early Adolescent Bipolar Disorder Geller, et al., JCAP 10:157-164, 2000

46. Bipolar Disorder: Symptoms • ~98% ADHD Dx prior to Mania • Unprovoked, unpremeditated aggression(Wozniak et al., 1994) • Tired in am, but then tantrums lasting 30min – 7 hrs • Energy accelerates over day, peaking pm • Nightmares of attack or abandonment (Papolos, 2000)

47. Pediatric-Onset Bipolar Disorder: Comorbid Conditions Percent Wozniak, J. data presented at MGH ADHD Course March 7-9, 2003 Boston, MA

48. ADHD and BPD: Results from 4-Year Follow-Up Study Overall rate of Bipolar Disorder Biederman J, et al. Arch Gen Psychiatry 53:437-46, 1996

49. Improvement of ADHD Before and After Improvement of Manic Symptoms The probability of ADHD improvement was 7.5 times higher following initial improvement in manic symptoms

50. Do SRIs Destabilize Manic Symptoms? • SRIs in children with a history of mania but no active manic symptoms significantly predicted deterioration of manic symptoms. • Subjects receiving an SSRI were three times as likely to develop manic symptoms at the next follow-up visit compared to subjects who had not received an SSRI (RR = 3.0 (1.2-7.8); p=0.02). (Biederman et al., JCAP 10 (3):185-192, 2000)