Table 1.
Characteristics of included meta-analyses or randomized controlled trials categorized by type of comorbidity and treatment
| Citation | Study design | ADHD diagnosis criteria | Key comorbidities | Primary efficacy measure | Treatment arms |
Patients enrolled or included in analysis | Mean age, years (SD) | Male (%) | Treatment duration | Relevant outcome measure(s) |
|---|---|---|---|---|---|---|---|---|---|---|
| Autism spectrum disorder: MPHs | ||||||||||
| Reichow, 2013 [19] | MA—3 trials reporting safety data [66, 84, 92] | NR | PDD—NR% | CPRS, CTRS, SNAP-IV, DSM-IV, ADHD general scales |
MPHs PBO |
NR | NR | NR | ≥ 1 week | Safety |
| Handen, 2000 [66] | RCT—crossover | ADHD symptoms |
Autistic disorder: 69.2% PDD-NOS: 30.8% ODD: 53.8%a |
NR | MPHs 0.3, 0.6 mg/kg, PBO | n = 13 | 7.4 (1.7) | 76.9 | 1 week each | Safety |
| Kim, 2017 [70] | RCT—parallel | K-SADS-PL |
Autistic disorder: 100% ODD: 37% |
ADHD-RS-IV |
MPHs 0.3 mg/kg MPHs 0.5 mg/kg |
n = 9 n = 18 |
9.3 (2.9) 9.1 (3.1) |
89 95 |
6 weeks | Safety |
|
Pearson, 2013 [43] |
RCT—crossover |
DSM-IV-TR + ADHD symptoms |
Autistic disorder: 79.2% PDD-NOS: 8.3% Asperger: 12.5% |
NR | MPHs 0.21, 0.35, 0.48 mg/kg, PBO | n = 24 | 8.8 (1.7) | 79.2 | 1 week each |
CGI-I, CGI-S Safety |
| RUPP, 2005 [84] | RCT—crossover | ADHD symptoms |
Autistic disorder: 71.2% PDD-NOS: 21.2% Asperger: 7.6% |
ABC—hyperactivity | MPHs 2.5–5, 2.5–10, 5–20 mg/kg, PBO |
n = 66 (RCT) n = 34 responders (OLE) |
7.5 (2.2) | 89.4 |
1 week each RCT + 8 weeks OLE |
Safety |
| Autism spectrum disorder: ATX | ||||||||||
| Patra, 2019 [18] | MA—3 trials [36, 38, 50] | ADHD symptoms | NR | Parent-rated ADHD symptoms, social behavior, serious adverse events | ATX, PBO | n = 241 | 9.3–10.0 | 75–80 | 6–10 weeks |
CGI-I Safety |
| Arnold, 2006 [50] | RCT—crossover | DSM-IV |
Autistic disorder: 43.8% PDD-NOS: 50% Asperger: 6.3% |
ABC hyperactivity | ATX, PBO | n = 16 | 9.3 (2.9) | 75.0 | 6 weeks each | Safety |
| Handen, 2015 [36] | RCT—parallel | ADHD symptoms |
Autistic disorder: 44.5% PDD-NOS: 39.1% Asperger: 16.4% |
SNAP-IV and Home Situations Questionnaire |
ATX + PT ATX PBO + PT PBO |
n = 32 for each group |
8.0 (1.9) 8.6 (2.3) 7.7 (1.5) 8.2 (2.4) |
96.9 81.3 84.4 78.1 |
10 weeks |
CGI-ADHD-I Safety |
|
Harfterkamp, 2012 [38] 2013 [67] |
RCT—parallel | DSM-IV-TR |
Autistic disorder: 59.8% PDD-NOS: 33.0% Asperger: 5.2% |
ADHD-RS-IV | ATX | n = 48 | 9.9 (2.7) | 87.5 | 8 weeks RCT | ADHD-RS-IV (INV) |
| PBO | n = 49 (RCT) | 10.0 (2.9) | 83.7 |
CGI-ADHD-I Safety |
||||||
| OLE | n = 88 (OLE) | 10.0 (2.9) | 86.3 | + 20 weeks OLE | Safety | |||||
| NCT00498173 [41] | RCT—parallel | ADHD symptoms |
Autistic disorder: 38.3% PDD-NOS: 38.3% Asperger: 23.3% |
ADHD-RS-IV |
ATX PBO |
n = 29 n = 31 |
9.3 (2.6) 8.4 (2.1) |
89.7 90.3 |
8 weeks |
ADHD-RS-IV (parent:INV) Safety |
| Autism spectrum disorder: GXR | ||||||||||
| Handen, 2008 [37] | RCT—crossover | ADHD symptoms | Intellectual disability or autism | NR | GXR, PBO | n = 11 | 7.3 (1.4) | 90.9 | 6 weeks |
CGI-I, CGI-S Safety |
| Scahill, 2015 [45] | RCT—parallel | ADHD symptoms |
Autistic disorder: 82.3% PDD-NOS: 14.5% Asperger: 3.2% |
ABC hyperactivity subscale—parent-rated |
GXR PBO |
n = 30 n = 32 |
8.5 (2.25) |
86.7 84.4 |
8 weeks |
ADHD-RS-IV (INV) CGI-I Safety |
| Oppositional defiant disorder: amphetamine | ||||||||||
| Spencer, 2006 [46] | RCT—parallel | NR | ODD: 79.2% | SNAP-IV ODD subscale |
AMPs PBO |
n = 248 n = 60 |
10.6 (2.8) 10.5 (3.0) |
68.5 71.7 |
4 weeks |
CGI-ADHD-I Safety |
| Oppositional defiant disorder: MPHs | ||||||||||
| Connor, 2000 [55] | RCT—parallel | DSM-III-R | ODD/CD: 100% | NR |
MPHs CLON MPHs + CLON |
n = 8 for each group |
8.9 (2.6) 9.3 (1.7) 10.1 (2.4) |
100 | 12 weeks | Safety |
| Jahangard, 2017 [68] | RCT—parallel | DSM-IV | ODD: 100% | NR |
MPHs MPHs + risperidone |
n = 42 for each group | 8.7 (1.3) |
76.2 71.4 |
8 weeks | Safety |
| Klorman, 1990 [71] | RCT—crossover | DSM-III |
ODD: 50% ODD + CD: 25% Adjustment disorder with depressive mood: 35.4% |
NR | MPHs, PBO | n = 48 | 14.1 (1.7) | 87.5 | 3 weeks each | Safety |
| Kolko, 1999 [72] | RCT—crossover | DSM-III-R |
ODD: 56% CD: 44% |
NR |
MPHs 0.3, 0.6 mg/kg PBO |
n = 22 | NR | 100 | 6 weeks | Safety |
| Oppositional defiant disorder: ATX | ||||||||||
| Cheng, 2007 [17] | MA—2 trials [39, 42] | NR | ODD: NR% | ADHD-RS-IV |
ATX PBO |
n = 137 n = 76 |
NR | NR | NR |
ADHD-RS-IV (parent:INV) CGI-S |
| Schwartz, 2014 [20] | MA—9 trials | NR |
ODD: various% |
ADHD-RS-IV parent-rated |
ATX PBO |
n = 2158 n = 1539 |
NR | NR | 4–18 weeks | ADHD-RS-IV (parent:INV) |
| Bangs, 2008 [30] | RCT—parallel | DSM-IV | ODD: 100% | SNAP-IV ODD subscale |
ATX PBO |
n = 156 n = 70 |
9.5 (1.9) 9.7 (1.9) |
91.7 97.1 |
8 weeks |
CGI-I, CGI-S Safety |
|
Dell’Agnello, 2009 [32] |
RCT—parallel | DSM-IV | ODD: 100% | SNAP-IV ADHD subscale |
ATX PBO |
n = 105 n = 32 |
9.7 (2.2) 10.0 (2.4) |
93.3 90.6 |
8 weeks |
CGI-ADHD-S Safety |
|
Dittman, 2011 [33] |
RCT—parallel | DSM-IV-TR | ODD: 100% | SNAP-IV ODD subscale |
ATX PBO |
n = 121 n = 59 |
10.9 (3.1) 11.1 (2.8) |
86.0 81.4 |
9 weeks |
CGI-S Safety |
| Garg, 2015 [63] | RCT—parallel | DSM-IV-TR | ODD: 100% | Vanderbilt ADHD Diagnostic Parent Rating Scale |
MPHs ATX |
n = 15 n = 22 |
8.7 (2.4) 9.1 (2.6) |
80.0 77.3 |
8 weeks | Safety |
| Kaplan, 2004 [39] | RCT—pooled | DSM-IV | ODD: 100% | ADHD-RS-IV |
ATX PBO |
n = 53 n = 45 |
9.8 (1.5) 10.2 (1.5) |
79.2 80.0 |
9 weeks |
ADHD-RS-IV (parent:INV) CGI-ADHD-I Safety |
| Newcorn, 2005 [42] | RCT—parallel | DSM-IV | ODD: 100% | ADHD-RS-IV | ATX 0.5 mg/kg | n = 21 | 11 (2.1) | 76.5 | 8 weeks |
ADHD-RS-IV (parent:INV) CGI-ADHD-S |
| ATX 1.2 mg/kg | n = 27 | |||||||||
| ATX 1.8 mg/kg | n = 34 | |||||||||
| PBO | n = 34 | |||||||||
| Oppositional defiant disorder: GXR | ||||||||||
|
Connor, 2010 [31] |
RCT—parallel | DSM-IV-TR | ODD: 100% | CPRS-R:L oppositional subscale |
GXR PBO |
n = 138 n = 79 |
9.4 (1.7) 9.3 (2.0) |
64.0 76.9 |
9 weeks |
ADHD-RS-IV (INV) Safety |
| Tourette’s disorder and other tic disorders: AMPs and MPHs | ||||||||||
| Bloch, 2009 [16] | MA—4 trials [40, 52, 61] | NR | Tic disorders: NR | Change in rating scales for tic and ADHD severity |
MPHs: NR PBO: NR |
n = 191 | NR | NR | NR | Safety |
| Castellanos, 1997 [52] | RCT—crossover | DSM-III-R |
Tourette: 95% Motor tic: 5% ODD: 30%a Enuresis: 20%a |
Tic severity (TSURS) and CTRS hyperactivity |
MPHs, AMPs, PBO | n = 20 | 9.4 (2.0) | 100 | 9 weeks | Safety |
| Gadow, 1999 [62]; Gadow, 2007 [61]; Gadow, 2011 [60] | RCT—crossover + OLE | DSM-III-R/ DSM-IV |
Tourette: 96% Motor tic: 4% |
YGTSS | MPHs 0.1, 0.3, 0.5 mg/kg | n = 71 (RCT) |
8.9 (1.9) 8.9 (1.9) |
80.3 91.2 |
6 weeks 2 years |
Safety |
| PBO | n = 34 (OLE) | |||||||||
| Law, 1999 [76] | RCT—parallel | DSM-III-R | Tics: 29.7% | Exacerbation or worsening of tic severity |
MPHs PBO |
n = 46 n = 45 |
8.4 (1.6) 8.3 (1.5) |
80.4 82.2 |
52 weeks | Safety |
| Tourette’s Syndrome Study Group, 2002 [40] | RCT—parallel | DSM-IV |
Tourette: 94% Motor tic: 5% Vocal tic: 0.8% ODD: 38%a |
CASQ-T |
MPHs CLON MPHs + CLON PBO |
n = 37 n = 34 n = 33 n = 32 |
10.7 (2.0) 9.7 (1.8) 10.6 (1.9) 9.7 (1.8) |
92 85 73 91 |
8 weeks |
CGI-ADHD-I Safety |
| Tourette’s disorder and other tic disorders: ATX | ||||||||||
| Allen, 2005 [28] | RCT—parallel | DSM-IV |
Tourette: 79.1% Motor tic: 29.7% Vocal tic: 17.6% ODD: 21.6%a |
YGTSS total score |
ATX PBO |
n = 76 n = 72 |
10.9 (2.5) 11.5 (2.4) |
92.1 84.7 |
18 weeks |
ADHD-RS-IV (parent:INV) CGI-S Safety |
| Tourette’s disorder and other tic disorders: GXR | ||||||||||
| Scahill, 2001 [44] | RCT—parallel | DSM-IV |
Tourette: 59.0% Motor tic: 35.3% |
NR |
GXR PBO |
n = 17 for each group | 10.4 (2.0) | 91.2 | 8 weeks |
ADHD-RS-IV (teacher:INV) CGI-I Safety |
| Generalized anxiety disorder and/or major depressive disorder: MPHs | ||||||||||
| Abikoff, 2005 [48] | RCT—parallel | DSM-IV |
Generalized anxiety: 78–100% Separation anxiety: 50–80% Social phobia: 28–30% ODD: 25–29% |
SNAP-IV ADHD subscale PARS |
MPHs MPHs + fluvoxamine |
n = 8 n = 12 |
10.8 (2.6) 10.4 (2.7) |
NR | 8 weeks | Safety |
| Diamond, 1999 [56] | RCT—parallel | DSM-III-R | Anxiety: 41.8% | NR | + Anxiety | + Anxiety | 16 weeks | Safety | ||
| MPHs | n = 19 for | 8.7 (1.8) | 78.9 | |||||||
| PBO | each group | 8.1 (1.3) | 73.7 | |||||||
| − Anxiety | − Anxiety | |||||||||
| MPHs | n = 27 | 8.2 (1.5) | 81.5 | |||||||
| PBO | n = 26 | 8.4 (1.6) | 88.5 | |||||||
| Generalized anxiety disorder and/or major depressive disorder: ATX | ||||||||||
| Bangs, 2007 [29] | RCT—parallel | DSM-IV | MDD: 100% |
ADHD-RS-IV CDRS-R |
ATX PBO |
n = 72 n = 70 |
14.6 (1.8) 14.2 (1.5) |
72.2 74.3 |
9 weeks |
ADHD-RS-IV (parent:INV) CGI-S, CGI-I Safety |
| Geller, 2007 [34] | RCT—parallel | DSM-IV | Anxiety: 100% |
ADHD-RS-IV PARS |
ATX PBO |
n = 55 n = 58 |
12.2 (2.8) 11.8 (2.5) |
62.1 67.4 |
12 weeks |
ADHD-RS-IV (INV) CGI-S Safety |
| Griffiths, 2018 [35] | RCT—crossover | DSM-IV |
Anxiety: 100% ODD: 55.3%a |
Response inhibition, sustained attention, fearful facial emotion | ATX, PBO | n = 38 | 11.2 (2.7) | 73.7 | 6 weeks each | ADHD-RS-IV (parent:INV) |
| Kratochvil, 2005 [73] | RCT—parallel | DSM-IV |
MDD: 45.7% Other mood: 15.6% Generalized anxiety: 33.5% |
Safety and tolerability |
ATX ATX + fluoxetine |
n = 46 n = 127 |
11.6 (2.4) 11.2 (2.7) |
65.2 74.8 |
5 weeks | Safety |
ABC Aberrant Behavior Checklist, ADHD attention-deficit hyperactivity disorder, ADHD-RS-IV ADHD Rating Scale IV, AMPs amphetamine or a derivative, ATX atomoxetine, CASQ-T Conners’ Abbreviated Symptom Questionnaire-Teacher, CD conduct disorder, CDRS-R Children’s Depression Rating Scale-Revised, CGI-I Clinical Global Impression-Improvement, CGI-S Clinical Global Impression-Severity, CLON clonidine, CPRS-R:L Conners’ Parent Rating Scale-Revised-Long Form, CPRS Conners’ Parent Rating Scale, CTRS Conners’ Teacher Rating Scale, DSM-III-R Diagnostic and Statistical Manual of Mental Disorders-3rd Edition Revised, DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders-4th Edition Text Revision, ER extended release, GXR guanfacine extended-release, INV investigator, K-SADS-PL Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime, MA meta-analysis, MDD major depressive disorder, MPHs methylphenidate or a derivative, NR not reported, ODD oppositional defiant disorder, OLE open-label extension, PARS Pediatric Anxiety Rating Scale, PBO placebo, PDD-NOS pervasive developmental disorder-not otherwise specified, PT parent training, RCT randomized controlled trial, SD standard deviation, SNAP-IV Swanson, Nolan, and Pelham Rating Scale-Revised, TSURS Tourette Syndrome Unified Rating Scale, YGTSS Yale Global Tic Severity Scale
aIn addition to the comorbidity of interest and reported in ≥ 20% of patients