1. Long-term Effects of Mental Health Interventions in Children Benedetto Vitiello, M.D. Roma, 11 May 2012

2. Disclosure I have no financial conflicts of interest The views here presented are not official statements of NIMH/NIH

3. Prominence of mental illness in childhood Leading causes of burden of disease for age under 15 years, in high-income countries: 1. Neuropsychiatric disorders 2. Perinatal conditions 3. Unintentional injuries (WHO 2004)

4. Psychopathology during development Autism spectrum disorders affect about 0.5% of children Anxiety disorders often start in childhood About one third of all cases of schizophrenia start below age 18

5. Age of onset of mood disorders (Kessler et al., 2005) DepressionIn 25% of cases, onset by age 19 In 10% of cases, onset by age 14 In 5% of cases, onset by age 12 BipolarIn 25% of cases, onset by age 17 In 10% of cases, onset by age 13 In 5% of cases, onset by age 11

6. Most common causes of hospitalization in the U.S. (Lasky et al. 2011) Age 10-14 yr: 1. Appendicitis 2. Mood disorders 3. Asthma Age 15-17 yr: 1. Mood disorders 2. Obstetrics 3. Traumas

7. Aims of this presentation: To review the developmental context for mental health interventions To discuss the effectiveness of commonly used child psychiatry treatments To highlight areas of ongoing research

8. Importance of a long-term perspective Most psychiatric disorders are chronic or recurrent, and require long-term treatment Early intervention may be the only opportunity to improve life long prognosis Chronic treatment can have unwanted effects

9. We need to consider the trajectory of psychopathology in order to: To understand the meaning of the symptom To plan targeted therapeutic interventions

10. ADHD trajectory with age (Faraone et al. 2006)

11. Treatment effectiveness: the best source of evidence Type I: strong evidence from at least one systematic review of multiple well-designed randomized controlled trials (RCT) Type II: strong evidence from at least one properly designed RCT of appropriate size [Gray, 1997]

12. Treatment effect size (vs. a control) 0.3 small effect size 0.5medium effect size 0.8 large effect size

13. Effective treatments of ADHD Effect size NNT Behavior therapymedium 6 Stimulants (methylphenidate, amphet.) large 3 Atomoxetinemedium 6 Alpha-2 agonistsmedium 6

14. Stimulants are highly effective at decreasing ADHD symptoms Highest level of evidence: Type I: strong evidence from meta-analyses and systematic reviews of multiple RCTs. Well documented by numerous placebo-controlled studies (both crossover and parallel-group designs)

15. Methylphenidate: Effects Effect size vs. placebo: Teacher-rated inattention/hyperactivity: 1.31 Parent-rated inattention/hyperactivity: 0.63 Response rate: 77% on MPH 12.5% on Placebo  NNT=1.5 [MTA Study]

16. Pediatric stimulant use in the U.S., 1987-2008 (Zuvekas & Vitiello, 2012)

17. 14-Month Outcomes Teacher SNAP-Inattention Average Score Assessment Point (Days)

18. Normative comparison group

19. Treatment of ADHD Effective at improving attention and decreasing impulsivity/hyperactivity Effective at improving performance on academic work and tests  How effective at improving learning?  How effective in changing the trajectory of psychopathology and improve distal prognosis?

20. ADHD Medication and School Achievement (Scheffler et al. 2009) Early Childhood Longitudinal Study N=594 children with ADHD 5 surveys between kindergarten and 5 th grade Children treated with medication had a mean math score greater than untreated children, after controlling for confounding variables

21. Stimulant medication improves driving on simulator (Kay et al., 2009)

22. Stimulant improves road driving (Verster et al., 2008) N=18 Randomized, placebo-controlled cross-over Methylphenidate 10-30 mg Primary measure: weaving of the car (SD of lateral position: 21.1 on placebo vs. 18.8 on MPH (p=.004)

23. Long-term safety of stimulants

24. Stimulants and growth Group Rx DoseHeight Growth (mean mg/day) (mean cm/14 months) Beh06.19 CC23 5.68 Comb31 4.95 Med only384.75 Behav - Med = 1.23 cm/year [MTA Cooperative Group, Pediatrics 2004;113:762-9 ]

25. Chronic MPH in juvenile male rhesus monkeys (Mattison et al., 2011) Methylphenidate 2.5 mg/kg/day (N=10) Plasma levels: 4-14 ng/mL Methylphenidate 12.5 mg/kg/day (N=10) Plasma levels: 50-200 ng/mL Control: saline (N=10) Treatment: 5 days a week Duration: 33 months

26. Pubertal delay in male monkeys treated with methylphenidate (Mattison et al., 2011)

27. Stimulants and cardiovascular function Average increase in: Heart rate: 2-6 bmp Systolic BP: 2-4 mmHg Diastolic BP: 1-3 mmHg

28. Stimulants treatment for 10 years (Vitiello et al., 2012) Average increase in: Heart rate: 2-6 bmp Systolic BP: 2-4 mmHg Diastolic BP: 1-3 mmHg during chronic treatment

30. Stimulants and risk for hypertension after 10 years of treatment (Vitiello et al., 2012)

31. Cumulative 10-year exposure to stimulant and risk for hypertension (Vitiello et al., 2011) Cumulative doseN % 95% C.I. 05018.0 6.2 - 29.8 1-7,8982619.2 2.4 - 36.1 7,899-43,46010023.0 13.6-32.4 >43,46016921.3 14.3-28.3

32. After 10 yrs of stimulant treatment (Vitiello et al., 2011) Current N HR SD use No medNo5068.911.0 Cum < 7,898 mgNo2670.214.7 Cum 7,899-43,460 mgNo9868.111.3 Yes 282.05.7 Cum >43,460 mgNo14570.711.1 Yes2473.710.4

33. Depression and development When negative thoughts become depression Often preceded by anxiety disorder Much more common after puberty – 1.4% at age 8-11 vs. 3.2% at age 12-15 Episodic and recurrent – cumulative prevalence: 11.7% by age 18) Predicts mood disorder in adulthood

34. Natural history of self-harm: a population- based cohort study (Moran et al., 2012)

35. Treatment of depression in youth: how effective? CBT: ES=0.34 (Weisz et al. 2006) SSRIs: ES=0.25 (Bridge et al. 2007) Response rate: 61% on med. vs. 50% on placebo  NNT=10

36. TADS (N=439, age 12-17) T A D S

37. Depression scores over 9 months T A D S

38. Antidepressant in children: how safe? (Bridge et al. 2007) Rate of suicidal ideation/suicide attempts: SSRI: 3% (CI 95%, 2 to 4%) PBO: 2% (CI 95%, 1 to 2%)  NNH=112

39. Bipolar disorder (“extreme mood dysregulation”) and its treatment TEAM: randomized trial of risperidone, lithium, and valproate N=279 – 6-15 yr (mean 10), 50% males, 73% white Five U.S. universities 8 weeks Open but with blinded clinical raters at baseline and end of study (week 8)

40. TEAM: Improvement rate at week 8 (Geller et al. 2012)

41. Schizophrenia: a developmental disorder

42. Progressive brain volume loss in the early phase of schizophrenia (Sporn et al., 2003)

43. Can early antipsychotic treatment improve the prognosis of schizophrenia? Duration of untreated psychosis predicts outcome Prognosis depends on level of functioning at time of treatment But, antipsychotics do not stop the brain loss…

44. Conclusions There are effective psychiatric treatments for children with ADHD, mood and anxiety disorders These treatments can improve symptoms and functioning, but their long term impact is unclear Research is ongoing to develop disease modifying treatments