1. Randomized Controlled CTN Trial of OROS-MPH + CBT in Adolescents with ADHD and Substance Use Disorders Paula Riggs, M.D., Theresa Winhusen, PhD., Jeff Leimberger, PhD., Susan Mikulich-Gilbertson PhD., Robert Davies M.D., Marilyn Macdonald B.A. Background Adolescents with substance use disorders (SUDs) have a higher prevalence of ADHD (30%-50%) compared to adolescents in the general population (5%-10%), but little is known about the safety and efficacy of pharmacotherapy for ADHD in adolescents with co-occurring disorders Clinicians are reluctant to prescribe medications for ADHD in substance-involved adolescents due to their exclusion from pharmacotherapy trials, commonly first referring them for substance treatment. A number of studies have shown that such youths have poorer treatment outcomes We could find no previous controlled trials evaluating the impact of psychostimulant treatment on both ADHD and substance treatment outcomes in comorbid adolescents concurrently enrolled in substance treatment Methods Study Design: A randomized controlled multisite trial of OROS-MPH + CBT vs placebo + CBT conducted in NIDA’s CTN between March, 2006 and September, 2008 Participants: 303 adolescents (ages 13-18) meeting DSM IV criteria for ADHD at least 1 non-tobacco SUD. Intervention: 72 mg daily doseOROS-MPH or matching placebo Intervention: 72 mg daily dose OROS-MPH or matching placebo CBT- All participants received manual standardized, weekly, individual CBT targeting substance abuse during the 16 week trial DIAGNOSTIC ASSESSMENT The KSADS-E was administered by site study physicians or masters’ level clinicians to all participants to determine DSM- IV diagnosis of ADHD and other psychiatric diagnoses Comprehensive International Diagnostic Interview (CIDI) used to determine DSM-IV SUD diagnoses, 11 drug categories: alcohol, cannabis, cocaine, hallucinogens, inhalants, opiates, sedatives, phencyclidine, amphetamines, and club drugs. Results Study Flow Diagram Demographics Study Flow Diagram Demographics Methods OUTCOME MEASURES ADHD.: Primary Outcome Measure. The DSM-IV ADHD Rating Scale (ADHD-RS) scores, adolescent report, obtained at baseline and weekly Secondary ADHD outcome measures 1)Parent-rated DSM-IV ADHD-RS scores 8 and 16 weeks 2)Clinician Global Impression-Improvement (CGI-I) ratings of ADHD treatment response were obtained monthly ; score of 1 (very much improved) or 2 (much improved) compared to the participant’s baseline ADHD severity, Non- responders=CGI-I > 2 3) Adolescent Coping Questionnaire (ARCQ) items: “problem solving ability ” and “focused coping skills”, administered at 16 weeks study completion Substance Outcome Measures Primary = # days of past 28 day non-tobacco drug (TLFB) Secondary = Urine D rug Screening (UDS) = # negative urine drug screens Analytic Approach: Primary analyses were intent-to-treat (ITT, including all randomized study participants); The primary outcome variables for ADHD and SUD used likelihood based methods, i.e. mixed (random coefficient) models Results Baseline Clinical Characteristic Figure 2. Change in DSM IV ADHD-RS Scores by Treatment Group Figure 3. Trajectories of past 28-day drug use Clinically and statistically significant decrease in ADHD symptoms in both groups but no difference between groups Clinically and statistically significant decrease in days of drug use in both groups but no difference between groups OROS-MPH > # - UDS vs placebo (3.8 v 2.8 P<.05) OROS-MPH: > # with > 75% reduction in drug use v placebo (p=.08) Post-hoc Analyses Subjects treated with OROS-MPH + CBT had significantly greater improvement in “problem solving ability” and “focused coping skills” compared to placebo + CBT treatment ADHD treatment responders (CGI-I, 1 or 2), regardless of medication group assignment, had 2x negative UDS (median=5) non-responders (CGI-I >2; median=1; p <.0001) ADHD treatment responders had more days of abstinence (median=94) compared to non-responders (median=77; p <.001) Safety and Tolerability Overall, OROS-MPH was safe and well-tolerated; 96% of participants achieved 72mg daily dose Adverse side effects were mild and mostly transient despite non- abstinence in most participants. Conclusions Overall, OROS-MPH was well-tolerated; had low abuse liability; good safety profile despite non-abstinence. There was no difference between OROS-MPH and placebo on primary ADHD and substance outcome measures, However, secondary outcome measures suggested some added benefit of OROS-MPH compared to placebo based on lower parent-rated DSM-IV ADHD-RS scores at 8 and 16 weeks; greater improvement in adolescent- reported “problem-solving ability” and “focused coping skills”; more negative UDS and more subjects with > 75% reduction in drug use. Greater than expected reduction in ADHD symptoms in both groups suggests that CBT may have contributed to ADHD response consistent with findings from adult studies (Levin et al 2006; 2007). Treatment responders, regardless of medication assignment had twice as many negative UDS and more days of abstinence, suggesting that reduction in ADHD symptoms may be clinically important in helping comorbid youth achieve abstinence with or without pharmacotherapy. However if ADHD does not respond to CBT early in treatment, OROS-MPH may be considered, even in youths who have not yet achieved abstinence. Funded by: NIDA U10 DA013732 CTN * Baseline Characteristics