Table 2.

Clinical Trials in Adolescents with Comorbid Psychiatric and Substance Use Disorders

Clinical Trial	Aims	Sample	N	Design	Intervention and Comparator dosing (mg/day)	Behavioral Intervention	Outcome measures	Results
Comorbid MDD and SUDs
Cornelius et al., 2010	To evaluate the efficacy of fluoxetine for the treatment of depressive symptoms and cannabis use in youths with comorbid MDD and CUD	Treatment-seeking adolescents and young adults (ages 14-25) who meet DSM-IV criteria for current MDD and an CUD	70	12-week, double-blind, placebo- controlled, randomized, clinical trial	Fluoxetine, oral, 20 mg/day versus placebo	9 session manualized CBT/MET	Cannabis use (TLFB), Depression (BDI, HAM- D-27)	No significant group-by- time interactions were noted for any depression- related (BDI: F=0.4, p= ns; HAM-D-27: F=0.4, p=ns) or cannabis- related (days of cannabis use, F=1.3, p=ns; DSM- IV CUD symptom count, F=0.5, p= ns) outcome variables Both treatment groups demonstrated significant within-group improvement in depressive symptoms greater than 50% reduction in BDI (F=40.0, p<0.001) and HAM-D-27(F=30.7, p<0.001)] and in DSM- IV CUD diagnostic criteria(39% reduction, F=4.7, p=0.035) Fluoxetine was well tolerated No significant reduction in cannabis use days in either treatment group (F=1.4, p=ns)
Cornelius et al., 2009	To evaluate the efficacy of fluoxetine for the treatment of depressive symptoms and drinking in adolescents with comorbid MDD and AUD	Treatment-seeking adolescents (ages 15- 20) who meet DSM- IV criteria for current MDD and an AUD	50	12-week, double-blind, placebo- controlled, randomized, clinical trial	Fluoxetine, oral, 20 mg/day versus placebo	9 session CBT/MET	Alcohol use (TLFB), Depression (BDI, HAM- D-27)	No significant group-by- time interactions were noted for any depression- related (BDI: F=0.7,p=ns; HAM-D-27: F=0.4,p=ns) or drinking- related (TLFB, DSM-IV AUD Sx Ct, p’s=ns) outcome variables Both treatment groups demonstrated significant within-group reductions in depressive symptoms (BDI: F=4.3, p=0.019; HAM-D-27: F=6.4, p=0.003) and level of drinking (DSM-IV AUD Sx Ct (F=8.0, p=0.007) Fluoxetine was well tolerated Number of heavy drinking days was significantly associated with lack of remission of depressive symptoms (BDI score< 8) at both the midpoint (F=6.8, p=0.013) and end of the study (F=9.1, p=0.009)
Findling et al., 2009	To evaluate the efficacy of fluoxetine for the treatment of depressive symptoms in adolescents with comorbid depressive disorder and SUD	Treatment-seeking adolescents (ages 12- 17) with DSM-IV diagnosis of current MDD or other depressive disorder and a comorbid SUD	34	8-week, double-blind, placebo- controlled, randomized clinical trial	Fluoxetine, oral, 20 mg/day versus placebo	Continuation of their pre- randomization psychotherapy or if with no current psychotherapy offered a referral to community- based resources (e.g. Alcoholics Anonymous)	Depression (CDRS-R, BDI), positive UDS at weeks 2,4,8, and 12, clinical improvement (CGI, CGAS)	No significant fluoxetine versus placebo group × time interactions were noted for depressive symptoms (CDRS- R)(mean diff= 0.2, F=0.1, p=ns) or number of positive UDS (F=0.2, p=ns) at interim futility analysis after 50% of subjects had completed study
Riggs et al., 2007	To evaluate the efficacy of fluoxetine versus placebo for the treatment of MDD, SUD, and CD in adolescents	Treatment-seeking adolescents (ages 13- 19) meeting DSM-IV criteria for current MDD, lifetime CD, and at least one non- tobacco SUD	126	16-week, double-blind, placebo- controlled, randomized clinical trial	Fluoxetine, oral, 20 mg/day versus placebo	Individual manualized CBT sessions weekly	Depression (CDRS-R), clinical improvement (CGI), substance use (TLFB), UDS(weekly), CD (DSM-IV symptom count)	Fluoxetine + CBT compared to placebo + CBT was associated with a significantly greater reduction in depression rating (CDRS-R score) by week 12 and continuing through week 16 (mean diff=5.7, F=2.8, p=0.04, effect size = 0.78) but not for clinical improvement (CDI score 1 or 2)(76% vs. 67% of subjects, RR 1.1, p=ns) No significant between group differences were noted for days of non- tobacco substance use (F=1.9, p=ns, effect size= 0.07) or CD symptoms (F=1.9, p=ns, effect size=0.22)
Deas et al., 2000	To evaluate the safety, tolerability, and efficacy of sertraline in the treatment of adolescents with comorbid MDD and AUDs	Treatment-seeking adolescents (mean age 16.6 years), meeting DSM-IV criteria for current MDD and AUD, presenting to an outpatient substance abuse treatment center	10	12-week, double-blind, placebo- controlled, randomized, clinical trial	Sertraline, oral, flexible dosing, 25 to 100 mg/day versus placebo	Non- manualized, cognitive- behavioral group therapy	Alcohol use (TLFB), Depression (HAM-D)	No significant group-by- time interactions were noted for any depression- related or drinking- related outcome variables (p’s for all analyses=ns)
								Both treatment groups demonstrated significant within-group reduction in depressive symptoms (HAM-D: 9.8 point reduction, F=26.1, p<0.001) and level of drinking (21% reduction in drinking days, F=8.9, p=0.02; −4.7 drinks per day, F=20.8, p=0.002) Sertraline was safe and well tolerated Depression responders tended to have higher alcohol use at baseline and reduction in depressive symptoms was associated with reduction in alcohol use (r=0.57, p=0.09)
Comorbid Bipolar Disorder and SUDs
Geller et al., 1998	To evaluate the safety, tolerability, and efficacy of pharmacokinetically- dosed Lithium for treatment of adolescents with Bipolar Disorder and Substance Dependence Disorders	Treatment-seeking adolescents (ages 12- 18) with DSM-III diagnosis of Bipolar Disorder and Substance Dependency Disorder (88% AUDs)	25	6-week, double-blind, placebo- controlled, randomized, clinical trial	Lithium pharmacokinetically- dosed to allow for 4- weeks at maintenace lithium levels of 0.9- 1.3 mEq/L versus placebo (dosed in parallel to Lithium)	Interpersonal therapy weekly	Alcohol and other drug use outcomes measured by urine drug screens, clinical improvement (CGAS)	On both ITT and completer analyses, Lithium group had significantly fewer positive UDS (χ2=4.8, p=0.03) and exhibited greater global clinical improvement (F=5.3, p=0.034) while outcomes related to mood did not differ between the groups
								Active responders mean serum lithium level was 0.9 mEq/L
								Significant differences were noted in side effects between the lithium and placebo group for thirst, polyuria, nausea, vomiting, and dizziness
Comorbid ADHD and SUDs
Riggs et al., 2011	To evaluate the safety and efficacy of OROS-MPH for treatment of ADHD symptoms and substance use in adolescent ADHD and SUD	Treatment-seeking adolescents (ages 13- 19) who meet DSM- IV criteria for ADHD (current) and at least one non-tobacco SUD	303	16-week, double-blind, placebo- controlled, randomized, multi-site, clinical trial	OROS-MPH, oral, 72 mg/day (or highest dose tolerated) titrated to dose over 2 weeks versus placebo	Individual manualized CBT weekly	ADHD-RS (primary), days of non- tobacco substance use in past 28 days (TLFB) (primary), ADHD-RS Parent form (secondary), negative UDS (secondary), CGI (secondary)	On ITT analyses, no significant group-by- time interactions were noted for primary outcome measures for ADHD (p=ns) or substance use (χ2=3.5, p=ns).
								Both OROS-MPH/CBT and placebo/CBT groups demonstrated significant within-group improvements in ADHD symptoms (ADHD-RS Score: −19.2 vs. −21.2, both p<0.001) and level of substance use (number of nontobacco substance use days: −5.7 vs. −5.2, both p<0.001) OROS-MPH + CBT as compared to placebo + CBT was associated with significant reductions in secondary outcome measures for ADHD (ADHD-RS Parent Score: mean diff 6.7 p<0.001) and substance use (negative UDS: 3.8 vs. 2.8 p=0.05, effect size=0.22)
								OROS-MPH was well tolerated but was associated with more adverse events (2.4 vs. 1.6 events, p=0.02) No differences were noted in abuse/misuse or diversion of study medication
Thurstone et al., 2010	To evaluate the safety efficacy of atomoxetine for the treatment of ADHD symptoms and substance use in adolescent ADHD and SUD	Treatment-seeking Adolescents (ages 13- 19) who meet DSM- IV criteria for ADHD (current) and at least one non-tobacco SUD	70	12-week, double-blind, placebo- controlled, randomized, clinical trial	Atomoxetine, oral, 100 mg/day (or 1.1- 1.5mg/kg if the participant weighed less than 70kg), titrated to dose over three weeks versus placebo	Individual manualized MI/CBT weekly	ADHD-CL- Clinician (primary), days of non- tobacco substance use in past 28 days (TLFB) (primary), ADHD-CL Parent form (secondary, negative UDS (secondary)	No significant group-by- time interactions were noted for any ADHD or substance use primary or secondary outcome variables (all analyses p’s=ns)
								Both Atomoxetine/MI- CBT and placebo/MI- CBT groups demonstrated significant within-group reductions in ADHD-CL-Clinician (overall reduction of 18.6 points, t=−10.6, p<0.001) and days of non-tobacco substance use between baseline and week 12 (−4.0 days, t=− 3.3, p=0.0015) Atomoxetine was well tolerated
Szobot et al., 2008	To evaluate the safety and efficacy of escalated doses of MPH-SODAS for treatment of ADHD symptoms in an outpatient sample of adolescents with ADHD and SUD	Treatment-seeking adolescent males (ages 15-21) with DSM-IV diagnosis of ADHD (current) and SUD (cannabis or cocaine)	16	6-week, single-blind, placebo- controlled, randomized cross-over study (weeks 1-3 on MPH- SODAS or placebo and then cross- over for weeks 4-6 to opposite study medication)	MPH-SODAS, oral, in escalating doses of 0.3, 0.7, and 1.2 mg/kg/day for weeks 1, 2, and 3 of active study medication versus placebo	None	SNAP-IV (primary), CGI (primary), number of days of drug use per week (secondary), number of smoked cannabis cigarettes (weekly) (secondary), and UDS (weeks 3,6) (secondary)	Significant MPH- SODAS compared to placebo treatment effect were noted on ADHD symptoms (SNAP-IV: F=42.9, p<0.001) and clinical improvement (CGI: F=25.3, p<0.001) with no significant sequence or period effects
								No significant MPH- SODAS versus placebo treatment, sequence, or period effects were observed for any drug use outcome variables (days of drug use per week, cannabis cigarettes smoked per week, and positive UDS, p’s=ns) MPH-SODAS was well tolerated
Riggs et al., 2004	To evaluate the safety and efficacy of pemoline for treatment of ADHD and CD symptoms and substance use in adolescents with comorbid ADHD, CD, and SUDs	Treatment-seeking adolescents (ages 13- 19) meeting DSM-IV criteria for ADHD (current), CD (lifetime), and one non-tobacco SUD referred from outpatient settings and the community	69	12-week, double-blind, placebo- controlled, randomized clinical trial	Pemoline, oral, 75 to 112.5 mg/day dose (highest dose tolerated), titrated to dose over four weeks versus placebo	None	CGI-I (primary), CHI-Parent (primary), DSM-IV CD symptom count (primary), days of non- tobacco substance use in past 28 days (TLFB) (primary), negative UDS (primary)	Pemoline treatment compared to placebo was associated with a significant clinical improvement (CGI-I 1 or 2) in ADHD symptoms on ITT analysis (32 vs. 12 subjects, p=0.05, effect size 0.5) and on parent-rated ADHD symptoms (change in CHI-P: −22.5 vs. −10.8, p=0.01) on completers but not ITT analysis
								No significant between group differences were noted for days of non- tobacco substance use (− 1.3 vs. −0.7 days, p=ns), negative UDS (2.4 vs. 3.1, p=ns), or CD symptoms (−0.8 vs. −0.5, p=ns)
								Pemoline was well tolerated and no elevation in liver enzymes or serious adverse events were observed
Riggs et al., 1998	To evaluate the safety, tolerability, and efficacy of buproprion for treatment of ADHD symptoms in adolescents with ADHD, CD, and SUD	Treatment-seeking adolescents males (ages 14-17) meeting DSM-IV criteria for ADHD (current), CD (lifetime), and one non-tobacco SUD residing in a long- term unlocked residential treatment program	13	5-week, open- label, prospective, pilot study	Buproprion , oral, 300 mg/day, titrated to dose over two weeks, no comparator	None	CGI-S, CHI- Teacher	Buproprion treatment was associated with improvements in teacher-rated ADHD symptoms (CHI-T: 13% reduction, p<0.01) and clinician-rated improvement (CGI: 39% improvement, p<0.002) from baseline to week 5
								Buproprion was safe and well tolerated
Solhkhah et al., 2005	To evaluate the safety, tolerability, and efficacy of buproprion for outpatient treatment of attentional deficits and mood symptoms in adolescents with ADHD, a mood disorder, and SUD	Treatment-seeking outpatient adolescents (ages 12-19) meeting DSM-IV criteria for ADHD, a mood disorder, and a non- tobacco SUD referred for outpatient treatment	14	6-month, open-label, naturalistic study with retrospective analysis	Buproprion SR, oral, started at 100mg once-daily and titrated up to a maximum dose of 400mg once-daily over 6 months (average dose 307mg/day at six months), no comparator	Monthly outpatient appointments over the six months but no formal psychotherapy	ADHD-CL, HAM-D, DUSI-R, CGI scores for Substance abuse, ADHD, Anxiety, Depression at baseline, 3- months, and 6-months	Buproprion SR treatment was associated with significant within-group reductions in substance use (DUSI-R: 39% reduction, p<0.05), ADHD (ADHD-CL: 43% reduction, p<0.001), and depression (HAM-D: 76% reduction, p<0.001) symptoms and clinical improvements (CGI) for ADHD (p<0.001), MDD (p<0.001), and SUDs (p<0.05) 13 of 14 subjects completed the 6-month study
								Buproprion SR was well tolerated with no significant adverse events

Abbreviations: ADHD= attention deficit/hyperactivity disorder, ADHD-CL-C= ADHD checklist-clinician administered (American Psychiatric Association, DSM 4^th Edition, 1994), ADHD-CL-P= ADHD checklist-parent form (American Psychiatric Association, DSM 4^th Edition, 1994), ADHD-RS-C= ADHD rating scale-clinician administered (DuPaul et al., 1998), ADHD-RS-P= ADHD rating scale-parent form (DuPaul et al., 1998), AUD= alcohol use disorder, BDI= Beck depression inventory (Beck, 1972), CD= conduct disorder, CDRS-R = children’s depression rating scale-revised (Poznanski et al., 1985), CGAS = children’s global assessment scale (Shaffer et al., 1983), CGI = clinical global impression scale with subscales for severity (CGI-S) and improvement (CGI-I) (NIMH, 1985), CHI-P= Connor’s hyperactivity impulsivity scale-parent form, a subscale of the Connor’s ADHD rating scale (Connors et al., 1998), CHI-T= Connor’s hyperactivity impulsivity scale-teacher form, a subscale of the Connor’s ADHD rating scale (Connors et al., 1998), CUD=cannabis use disorder, DUSI-R= drug use screening inventory-revised (Tartar et al., 1992), HAM-D = Hamilton depression scale (Hamilton, 1960), HAM-D-27= Hamilton depression scale-27 item version, ITT= intention to treat, MDD=major depressive disorder, MI/CBT= motivational interviewing/cognitive behavioral therapy, MPH-SODAS= spheroidal oral drug absorption system methylphenidate, OR=odds ratio, OROS-MPH= osmotically-controlled release oral delivery system methylphenidate, RR= relative risk, SNAP-IV= Swanson, Nolan, Pelham scale (Swanson, 1992), SR= sustained release, SUD= substance use disorder, Sx Ct= symptom count, TLFB= time line follow-back (Sobell et al., 1988), UDS= urine drug screen