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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.
Results
Background
Methods
• 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
OUTCOME MEASURES
• 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 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 DSMIV 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.
Baseline Characteristics
Variable
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, Nonresponders=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
Results
Study Flow Diagram
Demographics
Characteristics
OROS-MPH
(N-151
Placebo
(N=152)
All
(N=303)
122/151 (80.8%)
117/152 (77.0%)
239/303 (78.9%)
29/151 (19.2%)
35/152 (23.0%)
64/303 (21.1%)
16.4 (1.3)
16.6 (1.2)
16.5 (1.3)
95/148 (64.2%)
89/150 (59.3%)
184/298 (61.7%)
38/150 (25.3%)
69/298 (23.2%)
Sex
Male
Female
Age
Mean (SD)
Race*
Caucasian
African American
31/148 (20.9%)
Native American
2/148 (1.4%)
1/150 (0.7%)
3/298 (1.0%)
Asian
3/148 (2.0%)
1/150 (0.7%)
4/298 (1.3%)
Pacific Islander
0/148 (0.0%)
0/150 (0.0%)
0/298 (0.0%)
Other
8/148 (5.4%)
10/150 (6.7%)
18/298 (6.0%)
9/148 (6.1%)
11/150 (7.3%)
20/298 (6.7%)
23/151 (15.2%)
23/152 (15.1%)
46/303 (15.2%)
Mixed Race
Ethnicity
Hispanic
*Race was not indicated for 5 participants
Funded by: NIDA U10 DA013732
CTN
*
OROS-MPH/CBT Placebo/CBT
N=151
N=152
Baseline Clinical38.1(9.0)
Characteristic
39.3 (8.8)
ADHD severity
ADHD-RS
ADHD Diagnostic Subtype
1. Combined
2. Inattentive
3. HI
4. NOS
Substance Severity
No. days nontobacco
substance use/28 days
a
Total
N=303
38.7 ( 8.9 )
104 (68.9%)
43 (28.5%)
4 (2.6%)
0 (0%)
104 (68.4%)
42 (27.6%)
4 (2.6%)
2 (1.3%)
208 (68.6)
85 (28.1%)
8 (2.6%)
2 (0.7%)
14 (9.6)
15.1 (9.4)
14.6 (9.5)
# nontobacco
abuse/dependence diagnoses
Abuse and dependence
diagnoses by substance No.(%)
Alcohol abuse
2.1 (1.2)
1.9(1.3)
2.0 (1.2)
40 (26.5%)
40 (26.3%)
80(26.4%)
Alcohol dependence
48 (31.8%)
42 (27.6% )
90 (29.7%)
Cannabis abuse
43(28.5%)
34 (22.4%)
77 (25.4%)
Cannabis dependence
95(62.9%)
107(70.4%)
202 (66.7%)
Cocaine abuse
3 (2.0%)
5 (3.3% )
8 (2.6%)
Cocaine dependence
11 (7.3)
11 (7.2%)
22 (7.3%)
6 (4.0%)
3 (2.0%)
9 (3.0%)
Amphetamine abuse
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
Figure 2. Change in DSM IV ADHD-RS Scores by Treatment Group
b
Amphetamine dependence
3 (2.0%)
1 (0.7%)
Hallucinogen abuse
11 (7.3%)
12 (7.9%)
23 (7.6%)
Hallucinogen dependence
11 (7.3%)
5 (3.3%)
16 (5.3%)
Opiate abuse
20 (13.2%)
17 (11.2%)
37 (12.2%)
Opiate dependence c
0(0%)
1 (0.7%)
1
Sedative abuse
14(9.3%)
8 (5.3%)
22 (7.3%)
Sedative dependence
5 (3.3%)
3 (2.0%)
8(2.6%)
Other abuse
1 (0.7%)
1 (0.7%)
2 (0.7%)
Other dependence
1 (0 .7%)
0 (0%)
1 (0.3%)
Major Depressive Disorder (MDD)
19 (12.6%)
19(12.5%)
38(12.5%)
Conduct Disorder (CD)
50 (33%)
48(32%)
98(32.3%)
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 nonabstinence in most participants.
Conclusions
Clinically and statistically significant decrease
in ADHD symptoms in both groups but no
difference between groups
Figure 3. Trajectories of past 28-day drug use
4 (1.3%)
(0.3%)
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)
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 adolescentreported “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.