Table 7KQ2. Summary of studies reporting interventions with pharmacological agents

StudyStudy Design

Quality Rating
N
Mean Age (SD)
% Male

Population
Interventions comparedLength of FollowupResults
EffectivenessSafety
Psychostimulants
Andriola, M 2000145Retrospective cohort

Weak
N = 500
Age (range): 7y (4 to 18)
Male: 70%
MPH vs. pemoline*12mImprovement MPH <pemoline

d/c’d re: ineffective
MPH 32%, pemoline 10%
d/c’d re: AE:
pemoline 22%, MPH 5%
Barbaresi, W 200659Retrospective cohort

Fair
N = 379
Age: 10.4y (3.6)
Male: 78%
MPH, DEX, levo + DEEX, pemoline*; converted to MPH equivalent unitsBirth to mean age 17.2y

Tx duration 3.5y ( + /− 3.1y)
73.1% favorable response to stim treatment
positive response to stim less likely for very young and for older adolescents
positive response to DEX boys>girls
AE DEX (10.0%) >MPH (6.1%)
No increase in AEs with higher doses of MPH or DEX;
AEs more common for very young and for older adolescents
Charach, A 200457
See also Law58
RCT, systematic f/u

Good
N = 91
Age: 8.4y (1.6)
Male: 81%
MPH vs. placebo, then On vs. Off stim meds12m RCT, followed by 4y systematic f/uchildren with high levels of BL symptoms showed most response to stim, remained on them longest, but remained symptomatic at 5 yearsMost common AE was loss of appetite across all time points
Findling, R 200564
See also
McGough J 200563
OLE of CT

Fair
N = 568
Age: 8.7y (1.8)
Male: 78%
10 to 30mg
MAS XR daily
24mNo assessment of ADHD symptoms presentedsmall increase in BP, not clinically significant no apparent dose response 34 TE ECG abnormalities, none clinically significant
Gadow, K 199962OLE of CT

Good
N = 34
Age: 8.8y (1.9)
Male: 91%

tic disorder
MPH24mBehavior improvedNS worsening of tics
NS change wght & hght %ile
Increased BP at 24m
Gillberg, C 199761Single- and double-blind relapse prevention trial

Good
N = 62
Age: 9y (1.6)
Male: 84%

Comorbidities = PDD & low IQ
Amphetamine vs. placebo12m relapse prevention trial following 3 m active Tx, Placebo withdrawal followup after 15 monthsSymptoms improved >40%; 29% on amph vs. 71% on placebo d/c’d trial Tx, following placebo withdrawal after month 15, parent report no deterioration, teacher report mild deterioration WISC-R improved

CPT changes primarily among older children (9 to 11y)
No increase in tic frequency or severity relative to placebo Hallucinations in 4 subjects (3 amph & 1 placebo)
Hoare, P 200660OLE of CT

Fair
N = 89
Age: 6 to 16y
Male: NR

Typically developing
OROS MPH
Stable dose levels; 18 vs. 36 vs. 54mg
12mSatisfaction 49% to 69% (GAS); Efficacy 49% to 71% (GAA); >effect in pts older, higher dose, & ADHD-I12% d/c’d re: AE

4 SAEs:
2 depression/suicidal
1 delusions
1 severe aggression
Law, S 199958
see also Charach57
RCT

Good
N = 91
Age: 8.4y (1.6)
Male: 81%

ADHD + tics
MPH vs. placebo in subjects12m2% on MPH vs. 60% on placebo switched to other arm of trialNo sig. change in tic frequency between subjects on MPH or placebo
McGough, J 200563
See also Findling64
OLE of CT

Good
N = 568
Age: 8.7y (1.8)
Male: 78%

Typically developing
MAS XR vs. no Tx or placebo prior to OLE24mSymptom improvement maintained with LT Tx; No Tx or placebo prior showed 30% decrease in subjects

1% d/c’d re: ineffective
15% d/c’d re: AE; Increased AE with higher dose

2 SAEs: convulsions
Nolan, EE 2010146RCT

Good
N = 19
Age: 12.3y (0.3)
Male: 95%

ADHD + tic
MPH or DEX vs. placebo1yTx with stimulants maintenance dose was associated with behavioral improvement in ADHDAbrupt withdrawal of stimulants after long-term maintenance therapy does not worsen tic frequency or severity
Smith, BH 1998144Retrospective cohort

Weak
N = 16
Children:
Age: 10.2y (1.5)
Adolesc:
Age: 12y (0.8)
Male: 100%

Typically developing
MPH + STP vs. STP + placeboMode 3y
Range 1 to 4y (time elapsed from childhood to adolescence)
MPH Effect size (children) >MPH Effect size (adolesc)none discussed
Weisler, R 200565OLE of CT

Fair
N = 223
Age: 29.8y (11.5)
Male: 59%

Typically developing
MAS XR24mNR no assessment of ADHD symptoms presented21% d/c’d re: AE 7 adults w/d due to cardiovascular AE
-

2 palpitations and/or tachycardia

-

5 with hypertension

small mean increase in BP, HR, not clinically significant
Atomoxetine (ATX)
Adler, L 200568OLE of CT

Fair
N = 385
Age: 42.4y (11.2)
Male: 56%

Typically developing
ATX14wk CT, followed by up to 97wks OLESymp improv>30%10.9% d/c’d re: AE
maintained over time
Impairmentimproved
Disabilityimproved
Buitelaar, J 200767

See also Michelson66
DB relapse prevention

Good
N = 416
Age: 6 to 15y
Male: 90%

Typically developing
ATX vs. Placebo6m relapse prevention trial following 1yr active TxRelapse prevention ATX >placebo
ATX relapse 2.5 %
Placebo relapse 12.2 %
No AE observed

growth normal in ATX group
Michelson, D 200466

See also Buitelaar67
DB relapse prevention trial

Good
N = 416
Age: 10.6y (2.3)
Male: 89%

Typically developing
ATX vs. Placebo12wk OL Tx, followed by 9m DB relapse prevention trialATX: 22.3% relapse
placebo: 37.9% relapse
AE: Gastroenteritis and pharyngitis ATX >placebo

slowed growth with ATX compared to placebo
Wernicke, J 200369OLE of CT

Fair
N = 169
Age: 10.7y (2.2)
Male: 73%

Typically developing
ATX vs. Placebominimum 1yr TxNR no assessment of ADHD symptoms presentedmean increases to BP, HR were small and not clinically significant

no evidence of increase in QT interval with increased dose of ATX, after correcting for HR
Guanfacine Extended Release (GXR)
Biederman, J 200870OLE of CT

Fair
N = 240
Age:10.5y (2.6)
Male: 77%

Typically developing
GXR24mSymp improvement maintained to 12 m;
Parent rated impairment 58.6% improved
d/c’d re: adverse event 22%; Headache, fatigue, somnolence & sedation most common, 7 subjects d/c’d due to CV AEs

3 TE abnormal ECGs, clinically significant (2 bradycardia, 1 junctional escape complex)
3 SAEs: 2 syncope, 1 orthostatic hypotension
Sallee, F 200971OLE of CT

Fair
N = 262
Age:10y (2.6)
Male: 73%

Typically developing
GXR vs. GXR + stim24mSymp improv maintained to 24m; CHQ improv maintained D/c’d re: ineffective
13% GXR monotherapy
2% GXR + stim
d/c’d re AE:
13.6% GXR monotherapy
5.7% GXR + stim co-therapy
28 TE abnormal ECGs; 2 clinically significant (1 bradycardia, 1 intraventricular delay)
9 SAEs: 5 syncope

Note: table reports effect size for studies included in quality assessment of data

*

removed from market in 2005 due to risk of liver toxicity

Abbreviations: %ile = percentile; ADHD-I: Attention Deficit Hyperactivity Disorder – Inattentive; AE-adverse events; amph = amphetamine; ATX = Atomoxetine; BL-baseline; BP = blood pressure; CGI-IS = Clinical Global Impressions-Impairment scale; CHQ = child health questionnaire; CP = Classroom performance; CPT = Conners parent total score; CT = Clinical Trial; CV = cerebrovascular; d/c’d = discontinued; DEX = dextamphetamine; diff = difference; DR = dose related; ECG- electrocardiogram; extended release; f/u = followup; freq = frequency; GAA = Global Assessment of Adequacy; GAS = Global Assessment Satisfaction; GXR = Guanfacine extended release; hght = height; IR MPH = methylphenidate; levo = levoamphetamine; LT = long-term; MAS XR = mixed amphetamine salts; MPH = methylphenidate; NS = no(t) statistical significance; OLE = Open Label Extension; OROS; PDD = pervasive development disorder; QT interval = measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle; RCR = retrospective chart review; RCT = randomized controlled trial; SAEs = Serious Adverse Events; stim = stimulant; STP = summer treatment program; Symp Improv = symptom improvement; TE = treatment emergent; Tx = treatment; vs = versus; w/d = withdrawal; WISC-R = Weschler Intelligence Scale for Children – Revised; wght = weight; y = year

removed from market in 2005 due to risk of liver toxicity

From: Results

Cover of Attention Deficit Hyperactivity Disorder
Attention Deficit Hyperactivity Disorder: Effectiveness of Treatment in At-Risk Preschoolers; Long-Term Effectiveness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment [Internet].
Comparative Effectiveness Reviews, No. 44.
Charach A, Dashti B, Carson P, et al.

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