Early Stimulant Exposure Impact on Later Substance Abuse:

A Longitudinal Study

F. Xavier Castellanos

Rachel Klein

Sal Mannuzza

John Moulton

NYU Child Study Center

The New York Longitudinal Sample

• Recruited 1970 – 1977

• Lower middle class Caucasians; > 90% male

• Initial ages 6 to 12 y

• Pervasively hyperactive (included blinded in- school observations)

• Excluded if primarily aggressive

• [Main source of DSM-III criteria for ADHD]

Treatment of ADHD in Childhood

• All subjects diagnosed by Rachel Klein

• All psychopharmacology managed by Don Klein

• Free treatment – research clinic

• Other options essentially unavailable

• Methylphenidate – mean 38 mg/day– Identical to MTA titration!

• Duration: 7 d to 5 y; mean 2.2 y

Conners Teacher Hyperactivity Rating & Parent SES

2.42.3

2.22.3 2.3

2.5

3.2

33.1

3.6

3.33.4

0

0.5

1

1.5

2

2.5

3

3.5

4

6 7 8 9 10 11

Age MPH Tx Began (yrs)

CTRS

SES

N's 40 44 27 23 23 14

WISC or WISC-R Full Scale IQ

106 105

107

100 100 99

80

85

90

95

100

105

110

115

120

6 7 8 9 10 11

Age MPH Tx Began (yrs)

FS IQ

N's 40 44 27 23 23 14

Zijdenbos, Giedd, Blumenthal, Paus, Rapoport, & Evans

How Do We Measure the Brain?

Template brain

Deformation field

Atlas defined ontemplate brain

Total Cerebral Volumes

700

800

900

1000

1100

1200

1300

1400

1500

0 5 10 15 20 25AGE (y)

mL

ADHD F

ADHD M

NV F

NV M

N=291; 544 scans

Total Cerebral Vol. Growth Curves

900

1000

1100

5 7 9 11 13 15 17 19 21Age (y)

mL

NV Males

ADHD Males

NV Females

ADHD Females

Controls > ADHD P<.003

Castellanos, JAMA 2002

1000

1020

1040

1060

1080

1100

1120

1140

1160

1180

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Age (years)

mL

ADHD MN NV

Total Cerebral Volume in HealthyHealthy ControlsControls, Medicated ADHD, and Initially Unmedicated

ADHD

800

900

1000

1100

1200

1300

1400

1500

3 5 7 9 11 13 15 17 19 21 23

Age

Vo

lum

e

Total White Matter, N=128

300

320

340

360

380

400

Unmedicated Medicated Controls

p= 0.02, d=.68

n=24 n=50 n=54

p=.08, d=.34

Total Gray Matter, N=128

680

690

700

710

720

730

740

750

Unmedicated Medicated Controls

p=0.01, d=.47p=.08 vs Controls, d=.47

n=24 n=50 n=54

Total White Matter

300

320

340

360

380

400

Unmedicated Medicated Controls

0.0006

0.000002

n=49 n=103 n=139

N=291

Early Normal White Matter Development

• Paus et al., 2001– Brain Res Bull

Normal White Matter Development - Adulthood

• Increases ~linearly to max at ~ age 44

• N=70 men• Cross-sectional• Frontal, temporal WM• Bartzokis et al., 2001

– Arch Gen Psychiatry

Enduring Stimulant Effects?

• Not on teacher or parent behavior ratings• Sensitization of accumbal circuitry?

– Predisposition to substance abuse?– Well documented in animal studies

• Alternatively: protective against substance abuse• Mechanism?

– Trophic effect on myelination?

NY Longitudinal Study – Next Phase

• Reassess outcome at middle adulthood – Mean age 39 y

• Interval substance abuse, psychiatric, functional outcomes

• Relate 3-T high-resolution structural MRI including diffusion tensor imaging to outcome– Comparison with prospective control group– Stratify by age treatment began

• NIDA – R01 DA-16979