Systematic evidence synthesis of treatments for ADHD in children and adolescents: indirect treatment comparisons of lisdexamfetamine with methylphenidate and atomoxetine

Figures & data

Figure 1. PRISMA diagram for study inclusion and exclusion. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT = randomized controlled clinical trial.

Figure 2. Network diagram of all trials included in the meta-analyses. ATX = atomoxetine; LDX = lisdexamfetamine; MPH-LA = methylphenidate long acting; MPH-intR = methylphenidate intermediate release; MPH-SA = methylphenidate short acting. Sources17–19,27,29–55.

Table 1. Summary of trial and baseline patient characteristics, by treatment.

Treatment	Number of Trial Arms	Age in Years, Mean^a (Range)	Percentage Females, Mean^a (Range)	Time Point of Analysis, Weeks (Range)	Mean^a Baseline ADHD-RS Total Score (Range)	Number of Fixed-Dose Trial Arms
All treatments	68	9.8 (4.4–14.8)	22.0 (0.0–36.7)	5.7 (2–12)	39.1 (31.0–43.9)	17 of 68
LDX	3	11.7 (8.9–14.6)	28.2 (21.2–30.7)	4.6 (4–7)	40.7 (37.6–43.9)	2 of 3
ATX	18	9.8 (6.1–11.3)	20.5 (6.7–29.4)	6.9 (3–12)	38.7 (32.2–42.1)	4 of 18
MPH-LA	8	9.5 (8.8–14.8)	25.3 (9.4–35.2)	4.3 (3–8)	39.7 (31.6–43.8)	1 of 8
MPH-intR	2	9.2 (9.0–9.5)	18.4 (17.4–19.4)	3.0 (3–3)	37.4 (37.4–37.6)	1 of 2
MPH-SA	10	9.1 (4.4–10.4)	16.7 (0.0–21.1)	5.3 (2–10)	38.6 (31.0–42.4)	2 of 10
Placebo	27	9.9 (4.5–14.5)	22.0 (2.9–36.7)	5.9 (2–12)	39.1 (31.0–43.9)	7 of 27

ADHD-RS = ADHD Rating Scale; ATX = atomoxetine; LDX = lisdexamfetamine; MPH-LA = methylphenidate long acting; MPH-intR = methylphenidate intermediate release; MPH-SA = methylphenidate short acting.

^aMeans are weighted averages from trial arms.

Figure 3. Forest plot of network meta-analysis relative risks for treatment response based on ADHD-RS and CGI-I. ADHD-RS = ADHD Rating Scale; ATX = atomoxetine; CGI-ADHD-S = Clinical Global Impressions–ADHD–Severity; CGI-I = Clinical Global Impression–Improvement scale; LDX = lisdexamfetamine; MPH-LA = methylphenidate long acting; MPH-intR = methylphenidate intermediate release; MPH-SA = methylphenidate short acting.

Figure 4. Forest plot of network meta-analysis relative risks for all-cause and adverse-event-related withdrawals. ATX = atomoxetine; LDX = lisdexamfetamine; MPH-LA = methylphenidate long acting; MPH-intR = methylphenidate intermediate release; MPH-SA = methylphenidate short acting.

Table 2. Effects of trial and patient characteristics used as covariates in network meta-analysis models.

Endpoint Analyzed	Covariate Included	Trials With Covariate	Covariate Effect Estimate (95% CI)	Covariate Statistical Significance
ADHD-RS Response	Mean age (years)	16 of 16	−0.303 (−0.552, −0.053)	P = 0.018
	Percentage of females	16 of 16	0.000 (−0.015, 0.016)	P = 0.959
	Mean baseline ADHD-RS total score	15 of 16	0.007 (−0.053, 0.067)	P = 0.823
CGI-I Response	Mean age (years)	20 of 20	−0.129 (−0.395, 0.137)	P = 0.343
	Percentage of females	19 of 20	−0.007 (−0.027, 0.012)	P = 0.467
All-Cause Withdrawals	Mean age (years)	28 of 28	−0.246 (−0.936, 0.445)	P = 0.486
	Percentage of females	27 of 28	−0.027 (−0.060, 0.006)	P = 0.104

ADHD-RS = ADHD Rating Scale; CGI-I = Clinical Global Impression–Improvement scale; CI = confidence interval.

Table 3. Reduced chi-squared statistics, by NMA model and inclusion or exclusion of covariates.

Endpoint	Full NMA	Mean Age (Years)	Percentage of Females	Mean Baseline ADHD-RS Total Score
ADHD-RS	1.44	1.27	1.44	1.52
ADHD-RS (≥25% Reductions Only)	1.53	ND	ND	ND
CGI-I	0.87	0.84	0.90	NA
CGI-I (Excluding CGI-ADHD-S)	0.86	ND	ND	NA
Withdrawal Due to Any Cause	0.35	0.36	0.38	NA
Withdrawal Due to Adverse Events	0.36	ND	ND	NA

ADHD-RS = ADHD Rating Scale; CGI-I = Clinical Global Impression–Improvement scale; NMA = network meta-analysis; NA = not applicable; ND = not done.

Table 4. Comparison of indirect evidence of NMA results with head-to-head estimates.

Treatment Comparison	Endpoint	Direct MA/H2H RR (95% CI)	AIC RR (95% CI)	Consistency Check p Value
LDX vs. MPH-LA	CGI-I response	1.288 (1.068–1.552)	1.133 (0.446–2.877)	0.791
	ADHD-RS response	1.231 (1.080–1.403)	1.185 (0.435–3.228)	0.942
ATX vs. MPH-LA	CGI-I response	0.770 (0.696–0.853)	0.927 (0.545–1.576)	0.501
	ADHD-RS response	0.849 (0.793–0.909)	0.940 (0.461–1.915)	0.781
MPH-SA vs. MPH-LA	CGI-I response	0.780 (0.631–0.964)	0.734 (0.406–1.327)	0.850
MPH-SA vs. MPH-intR	CGI-I response	1.152 (0.778–1.704)	1.256 (0.922–1.710)	0.733

ADHD-RS = ADHD Rating Scale; AIC = adjusted indirect comparison; ATX = atomoxetine; CGI-I = Clinical Global Impression–Improvement scale; CI = confidence interval; H2H = head-to-head; LDX = lisdexamfetamine; MA = meta-analysis; MPH-intR = methylphenidate intermediate release; MPH-LA = methylphenidate long acting; MPH-SA = methylphenidate short acting; RR = relative risk.

Table 5. Heterogeneity test results for direct meta-analyses of placebo-controlled trials.

Treatment Comparison	Heterogeneity Test p Value
	CGI-I	ADHD-RS
LDX vs. placebo	<0.001	<0.001
ATX vs. placebo	0.290	0.020
MPH-LA vs. placebo	0.020	<0.001
MPH-SA vs. placebo	0.680	NA^a
MPH-intR vs. placebo	0.560	NA^a

ADHD-RS = ADHD Rating Scale; ATX = atomoxetine; CGI-I = Clinical Global Impression–Improvement scale; LDX = lisdexamfetamine; MPH-intR = methylphenidate intermediate release; MPH-LA = methylphenidate long acting; MPH-SA = methylphenidate short acting; NA = not applicable.

^aNo ADHD-RS data were available for this treatment.

Spencer T, Heiligenstein JH, Biederman J, et al. Results from 2 proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2002;63:1140-7

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