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

Zijdenbos, Giedd, Blumenthal, Paus, Rapoport, & Evans How Do We Measure the Brain? Template brain Deformation field Atlas defined on template brain

Total Cerebral Volumes AGE (y) mL ADHD F ADHD M NV F NV M N=291; 544 scans

Total Cerebral Vol. Growth Curves Controls > ADHD P<.003 Castellanos, JAMA 2002

Age (years) mL ADHD MN NV HealthyControls Total Cerebral Volume in Healthy Controls, Medicated ADHD, and Initially Unmedicated ADHD

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