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Long-term Effects of Mental
Health Interventions in Children
Benedetto Vitiello, M.D.
Roma, 11 May 2012
Disclosure
I have no financial conflicts of interest
The views here presented are not official
statements of NIMH/NIH
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)
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
Age of onset of mood disorders
(Kessler et al., 2005)
Depression In 25% of cases, onset by age 19
In 10% of cases, onset by age 14
In 5% of cases, onset by age 12
Bipolar
In 25% of cases, onset by age 17
In 10% of cases, onset by age 13
In 5% of cases, onset by age 11
Most common causes of
hospitalization in the U.S.
Age 10-14 yr:
(Lasky et al. 2011)
Age 15-17 yr:
1.
Appendicitis
1.
Mood disorders
2.
Mood disorders
2.
Obstetrics
3.
Asthma
3.
Traumas
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
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
We need to consider the trajectory of
psychopathology in order to:

To understand the meaning of the symptom

To plan targeted therapeutic interventions
ADHD trajectory with age (Faraone et al. 2006)
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]
Treatment effect size (vs. a control)

0.3
small effect size

0.5
medium effect size

0.8
large effect size
Effective treatments of ADHD
Effect size
medium
NNT

Behavior therapy
6

Stimulants (methylphenidate, amphet.) large
3

Atomoxetine
medium
6

Alpha-2 agonists
medium
6
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)
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]
Pediatric stimulant use in the U.S., 1987-2008
(Zuvekas & Vitiello, 2012)
6
Number of Users per 100 Population
5
4
0-5
6-1
130-1
3
2
1
0
1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Year
14-Month Outcomes
Teacher SNAP-Inattention
3
Time x Tx: F=10.6, p<.0001
Site x Tx: F=0.9, ns
Site: F=2.7, p<.02
2.5
CC
Beh
Average Score
MedMgt
2
Comb
1.5
1
Comb, MedMgt > Beh, CC
0.5
0
0
100
200
300
400
Assessment Point (Days)
Normative comparison group
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?
ADHD Medication and School Achievement
(Scheffler et al. 2009)

Early Childhood Longitudinal Study

N=594 children with ADHD

5 surveys between kindergarten and 5th grade

Children treated with medication had a mean
math score greater than untreated children,
after controlling for confounding variables
Stimulant medication improves
driving on simulator (Kay et al., 2009)
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)
Long-term safety of stimulants
Stimulants and growth
Group
Rx Dose
Height Growth
(mean mg/day)
(mean cm/14 months)
Beh
0
6.19
CC
23
5.68
Comb
31
4.95
Med only
38
4.75
Behav - Med = 1.23 cm/year
[MTA Cooperative Group, Pediatrics 2004;113:762-9]
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
Pubertal delay in male monkeys treated with
methylphenidate (Mattison et al., 2011)
Stimulants and cardiovascular function
Average increase in:
•
Heart rate: 2-6 bmp
•
Systolic BP: 2-4 mmHg
•
Diastolic BP: 1-3 mmHg
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
Stimulants and risk for hypertension
after 10 years of treatment (Vitiello et al., 2012)
50
40
30
Hypertension
Pre-hypertension
20
10
0
Currently on stimulant (N=18)
Previously on stimulant
(N=275)
Never on stimulant (N=50)
Normative comparison
(N=211)
Cumulative 10-year exposure to stimulant
and risk for hypertension (Vitiello et al., 2011)
Cumulative dose
N
%
95% C.I.
0
50
18.0
6.2 - 29.8
1-7,898
26
19.2
2.4 - 36.1
7,899-43,460
100
23.0
13.6-32.4
>43,460
169
21.3
14.3-28.3
After 10 yrs of stimulant treatment
(Vitiello et al., 2011)
Current N
HR
SD
use

No med
No
50
68.9
11.0

Cum < 7,898 mg
No
26
70.2
14.7

Cum 7,899-43,460 mg
No
98
68.1
11.3
Yes
2
82.0
5.7
No
145
70.7
11.1
Yes
24
73.7
10.4

Cum >43,460 mg
Depression and development
When negative thoughts become depression

Often preceded by anxiety disorder

Much more common after puberty
–

Episodic and recurrent
–

1.4% at age 8-11 vs. 3.2% at age 12-15
cumulative prevalence: 11.7% by age 18)
Predicts mood disorder in adulthood
Natural history of self-harm: a populationbased cohort study
(Moran et al., 2012)
Treatment of depression in youth:
how effective?

CBT:
ES=0.34

SSRIs:
ES=0.25 (Bridge et al. 2007)
(Weisz et al. 2006)
Response rate: 61% on med. vs. 50% on placebo  NNT=10
TADS (N=439, age 12-17)
Mean CDRS Score - Adjusted
60
COMB
50
FLX
CBT
PBO
40
30
Baseline
Week 6
Week 12
TAD S
Depression scores over 9 months
65
Mean CDRS-R Score
OC: Unadjusted Data
55
COMB
FLX
45
CBT
PBO
35
25
Base
Wk6
Wk12
Wk18
Assessment
Wk24
Wk30
Wk36
TAD S
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
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)
TEAM: Improvement rate at week 8
(Geller et al. 2012)
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
65.6%
34.4%
Risperidone
(n=93)
Lithium
(n=93)
23.1%
Divalproex
(n=104)
Schizophrenia: a developmental disorder
Progressive brain volume loss
in the early phase of schizophrenia
(Sporn et al., 2003)
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…
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