Table 13, KQ2 summary of findings and strength of evidence for FDA-approved pharmacological interventions - ADHD Diagnosis and Treatment in Children and Adolescents

Table 13KQ2 summary of findings and strength of evidence for FDA-approved pharmacological interventions

Intervention and Comparison	Outcome	Number of Studies and Study Design	Findings	Reasons for Downgrading	SoE
KQ2 pharmacological vs control	Behavior	11 RCTs¹⁵⁴^, ²²⁴^, ²²⁶^, ²⁴⁸^, ³²¹^, ³⁸⁰^, ⁴³²^, ⁴⁶⁰^, ⁶⁰⁸^, ⁶¹⁰^, ⁶²²	Results favor intervention (SMD ‑0.62; CI −0.97, −0.27; 5 studies, n=523); RR 0.36; CI 0.17, 0.78; 1 study, n=66)	I	Low for benefit
KQ2 pharmacological vs control	Broadband measures	64 RCTs¹⁰⁹^, ¹³¹^, ¹³³^, ¹⁴⁴^, ¹⁴⁵^, ¹⁶¹^, ¹⁶⁴^, ¹⁹⁴^, ¹⁹⁵^, ²⁰²^, ²⁰⁵^, ²⁰⁷^, ²¹⁷^, ²²⁰^, ²⁴⁷^, ²⁷⁰^, ²⁷²^, ²⁷³^, ²⁸⁸^, ²⁹²^, ³⁰⁵^, ³²⁶^, ³⁴¹^, ³⁴⁸^, ³⁶¹^, ³⁷³^, ³⁷⁴^, ³⁷⁸^, ⁴¹⁴^, ⁴¹⁹^, ⁴²⁵^, ⁴³¹^, ⁴⁴²^, ⁴⁵²^–⁴⁵⁵^, ⁴⁵⁹^, ⁴⁶¹^, ⁴⁸¹^, ⁵¹¹^, ⁵³⁸^, ⁵⁵⁴^, ⁵⁵⁵^, ⁵⁵⁷^, ⁵⁷³^, ⁵⁹⁸^, ⁶¹¹^, ⁶¹²^, ⁶¹⁷^, ⁶¹⁹^, ⁶²³^, ⁶²⁶^, ⁶³⁴	Results favor intervention (SMD 0.57; CI 0.48, 0.67; 28 studies, n=4467; RR 0.51; CI 0.43, 0.60; 25 studies, n=3959)	-	High for benefit
KQ2 pharmacological vs control	ADHD symptoms	76 RCTs¹⁰⁸^, ¹⁰⁹^, ¹¹⁸^, ¹³¹^–¹³³^, ¹⁴⁴^, ¹⁴⁵^, ¹⁵⁴^, ¹⁶¹^, ¹⁶⁴^, ¹⁹³^–¹⁹⁵^, ²⁰²^, ²⁰⁵^, ²⁰⁷^, ²¹⁷^, ²²⁰^, ²²⁶^, ²⁴⁷^, ²⁴⁸^, ²⁷⁰^–²⁷³^, ²⁸⁸^, ²⁹²^, ³⁰⁵^, ³⁰⁶^, ³¹⁷^, ³²¹^, ³²⁶^, ³³⁷^, ³⁴¹^, ³⁴⁸^, ³⁶¹^, ³⁷³^, ³⁷⁴^, ³⁷⁸^, ³⁸³^, ⁴¹⁴^, ⁴¹⁹^, ⁴²⁵^, ⁴³¹^, ⁴³²^, ⁴⁴²^, ⁴⁵²^–⁴⁵⁵^, ⁴⁵⁹^–⁴⁶¹^, ⁴⁸¹^, ⁵¹¹^, ⁵²⁶^, ⁵³⁸^, ⁵⁴⁰^, ⁵⁵⁴^–⁵⁵⁷^, ⁵⁷³^, ⁵⁷⁵^, ⁵⁹⁸^, ⁶⁰⁸^, ⁶¹⁰^–⁶¹²^, ⁶¹⁷^, ⁶¹⁹^, ⁶²²^, ⁶²³^, ⁶²⁶^, ⁶³⁴	Results favor intervention (SMD −0.61; CI −0.69, −0.52; 49 studies, n=7685; RR 1.71, CI 1.33, 2.19; 13 studies, n=1918)	-	High for benefit
KQ2 stimulant augmentation vs stimulant alone	ADHD symptoms	5 RCTs²¹⁷^, ³²¹^, ³⁷³ ⁵⁹⁸^, ⁶²²	Results favor augmentation (SMD −0.26; CI −0,52, −0.19; 5 studies, n=724)	C	Low for larger effects with augmentation
KQ2 pharmacological vs control	Functional impairment	18 RCTs¹⁰⁹^, ¹³¹^, ¹⁶⁴^, ²⁰²^, ²⁰⁵^, ³⁸⁰^, ⁴³²^, ⁴⁵²^–⁴⁵⁵^, ⁴⁵⁹^, ⁴⁶¹^, ⁵⁸⁸^, ⁶¹⁸^, ⁶²²^, ⁶²³^, ⁶³⁴	Results favor intervention (SMD 0.50; CI 0.05, 0.96; 10 studies, n=1703)	C	Moderate for benefit
KQ2 pharmacological vs control	Acceptability of treatment	3 RCTs²⁰⁷^, ⁵⁷³^, ⁶¹⁰	Results favor alpha agonist intervention (RR 0.47; CI 0.32, 0.68; 1 study, n=198)	I	Insufficient
KQ2 pharmacological vs control	Academic performances	4 RCTs⁵²⁶^, ⁵⁸⁸^, ⁶¹⁸^, ⁶¹⁹	Results favor intervention (SMD −1.37; CI −1.72, −1.03; 1 study, n=156)	I	Low for benefit
KQ2 pharmacological vs control	Appetite suppression	57 RCTs¹⁰⁹^, ¹¹⁸^, ¹³¹^–¹³³^, ¹⁴⁴^, ¹⁴⁵^, ¹⁵⁴^, ¹⁶¹^, ¹⁶⁴^, ¹⁹³^–¹⁹⁵^, ²⁰²^, ²¹⁷^, ²²⁰^, ²⁴⁷^, ²⁴⁸^, ²⁷⁰^, ²⁷²^, ²⁷³^, ²⁸⁸^, ²⁹²^, ³⁰⁵^, ³¹⁷^, ³²¹^, ³²⁶^, ³⁴⁸^, ³⁶¹^, ³⁷⁸^, ³⁸³^, ⁴¹⁴^, ⁴¹⁹^, ⁴³¹^, ⁴³²^, ⁴⁴²^, ⁴⁵²^–⁴⁵⁵^, ⁴⁶⁰^, ⁴⁸¹^, ⁵¹¹^, ⁵³⁸^, ⁵⁵⁶^, ⁵⁵⁷^, ⁵⁷³^, ⁵⁷⁵^, ⁶⁰⁸^, ⁶¹⁰^–⁶¹²^, ⁶¹⁷^, ⁶¹⁸^, ⁶²²^, ⁶²⁶^, ⁶³⁴	Intervention is associated with appetite suppression (SMD 0.48; CI −0.04, 1.00; 6 studies, n=605; RR 3.51; CI 2.72, 4.51; 46 studies, n=7209)	-	High for increased risk
KQ2 pharmacological vs control	Participants with adverse events	42 RCTs¹³¹^, ¹⁴⁴^, ¹⁴⁵^, ¹⁵⁴^, ¹⁶¹^, ¹⁶⁴^, ¹⁹⁴^, ¹⁹⁵^, ²⁰²^, ²⁰⁵^, ²⁰⁷^, ²¹⁷^, ²⁴⁷^, ²⁴⁸^, ²⁷⁰^, ²⁷²^, ²⁷³^, ³⁰⁵^, ³¹⁷^, ³²⁶^, ³³⁷^, ³⁴¹^, ³⁷³^, ³⁷⁴^, ⁴¹⁴^, ⁴¹⁹^, ⁴²⁵^, ⁴⁴²^, ⁴⁵²^–⁴⁵⁴^, ⁴⁵⁹^, ⁵⁴⁰^, ⁵⁷³^, ⁵⁷⁵^, ⁵⁹⁸^, ⁶⁰⁸^, ⁶¹²^, ⁶²²^, ⁶²³^, ⁶²⁶^, ⁶³⁴	Pharmacological treatment is associated with a higher risk of reported adverse events (RR 1.29; CI 1.23, 1.35; 41 studies, n=6926)	-	High for increased risk
KQ2 CER non-stimulants vs stimulants	Behavior	N/A (indirect comparison)	Insufficient data	D, C	Insufficient
KQ2 CER amphetamine vs methylphenidate vs NRI vs alpha agonist	Behavior	NA (indirect comparison)	No difference detected (p 0.42)	D	Low for no difference
KQ2 CER atomoxetine vs methylphenidate	Behavior	5 RCTs¹⁷⁵^, ⁴⁶⁰^, ⁵⁰⁴^, ⁵¹²^, ⁵²⁵	NRIs showed more improvement than stimulants (SMD −0.08; CI −0.14, −0.03; 4 studies, n=608)	S	Low for larger effects in NRI atomoxetine
KQ2 CER non-stimulants vs stimulants	Broadband measures	N/A (indirect comparison)	Non-stimulant studies reported smaller effects than stimulant studies (non-stimulants RR 0.66; CI 0.58, 0.76; 12 studies, n=2312 vs stimulants RR 0.38; CI 0.30, 0.48; 12 studies, n=1582; p 0.0002)	D	Low for larger effects in stimulants
KQ2 CER amphetamine vs methylphenidate vs NRI vs alpha agonist	Broadband measures	N/A (indirect comparison)	Amphetamine studies found no statistically effect but reported the largest effects (SMD 0.68; CI −0.72, 2.08; 3 studies, n=561); methylphenidate studies favored intervention (SMD 0.66; 0.04, 1.28; 2 studies, n=302); NRI studies favored intervention (SMD 0.53; CI 0.44, 0.63; 20 studies, n=3183); alpha agonist studies favored intervention (SMD 0.45; CI 0.22, 0.68; 4 studies, n=509); p 0.002		Insufficient
KQ2 CER atomoxetine vs methylphenidate	Broadband measures	4 RCTs¹⁷⁵^, ⁴⁶⁰^, ⁵⁰⁴^, ⁵²⁵	No systematic difference (SMD ‑0.16; CI −0.35, 0.03; 4 studies, n=1080)	S, C	Low for no difference
KQ2 CER non-stimulants vs stimulants	ADHD symptoms	N/A (indirect comparison)	Non-stimulant studies reported smaller effects than stimulant studies (SMD −0.52; CI −0.59, −0.46; 37 studies, n=6065 vs SMD −0.88; CI −1.13, −0.63; 12 studies, n=1620; p 0.0002)	D	Low for larger effects in stimulants
KQ2 CER amphetamine vs methylphenidate vs NRI vs alpha agonist	ADHD symptoms	N/A (indirect comparison)	Amphetamine studies favored intervention (SMD −1.16; CI −1.64, −0.67; 5 studies, n=757); methylphenidate studies favored intervention (SMD −0.68; CI −0.91, −0.46; 7 studies, n=863); NRI studies favored intervention (SMD 0.55; CI −0.62, −0.47; 28 studies, n=1925); alpha agonist studies favored intervention (SMD 0.52; CI −0.67, −0.37; 11 studies, n=1885); p 0.04	D	Insufficient
KQ2 CER NRIs vs stimulants	ADHD symptoms	7 RCTs¹³⁷^, ²²⁵^, ³⁷⁶^, ⁴⁶⁰^, ⁵³⁹^, ⁶⁰⁴^, ⁶⁴⁵	No systematic difference (SMD 0.23; CI −0.03, 0.49; 7 studies, n=1611)	S, C	Low for no difference
KQ2 CER amphetamine vs methylphenidate	ADHD symptoms	1 RCT ¹³¹ (direct comparison), and N/A (indirect comparison)	A direct comparison shows more improvement with amphetamine vs methylphenidate (SMD −0.46; CI −0.73, −0.19; 1 study, n=222) and indirect comparisons show amphetamine studies reported more improvements than methylphenidate studies for continuous outcomes (SMD −1.16; CI −1.64, −0.67; 5 studies, n=757; SMD −0.68; CI −0.91, −0.46; 7 studies, n=863; p 0.02) but there was no systematic difference for categorical outcomes (p 0.57)	D, C	Low for larger effects of amphetamines
KQ2 CER NRI vs alpha agonists	ADHD symptoms	1 RCT ³²⁶ (direct comparison) and N/A (indirect comparison)	A direct comparison shows more improvement with atomoxetine (SMD −0.47; CI −0.73, −0.2; 1 study, n=226, indirect comparisons show no systematic difference (continuous p 0.90, categorical p 0.57)	C	Insufficient
KQ2 CER non-stimulants vs stimulants	Functional impairment	N/A (indirect comparison)	Non-stimulant studies reported smaller effects than stimulant studies (SMD 0.20; CI −0.05, 0.44; 6 studies, n=1163 vs SMD 1.00; CI −0.25, 2.26; 4 studies, n=540; p 0.04)	D	Low for larger effects in stimulants
KQ2 CER amphetamine vs methylphenidate vs NRI vs alpha agonist	Functional impairment	N/A (indirect comparison)	No difference detected (p 0.23)	D	Low for no difference
KQ2 CER non-stimulants vs stimulants	Acceptability of treatment	N/A (indirect comparison)	Insufficient data	D, C	Insufficient
KQ2 CER amphetamine vs methylphenidate vs NRI vs alpha agonist	Acceptability of treatment	N/A (indirect comparison)	Insufficient data	D, C	Insufficient
KQ2 CER non-stimulants vs stimulants	Academic performance	N/A (indirect comparison)	Insufficient data	D, C	Insufficient
KQ2 CER amphetamine vs methylphenidate vs NRI vs alpha agonist	Academic performance	N/A (indirect comparison)	Insufficient data	D, C	Insufficient
KQ2 CER non-stimulants vs stimulants	Appetite suppression	8 RCTs¹⁷⁵^, ²²⁵^, ³⁷⁶^, ⁵¹²^, ⁵³⁹^, ⁵⁶⁸^, ⁶⁴⁵	No systematic difference (RR 0.82; CI 0.53, 1.26; 8 studies, n=1463)	S	Low for no difference
KQ2 CER amphetamine vs methylphenidate vs NRI vs alpha agonist	Appetite suppression	N/A (indirect comparison)	Amphetamine studies reported an increased risk (RR 7.08; CI 2.72, 18.42; 8 studies, n=1229); methylphenidate studies reported an increased risk (RR 2.80; CI 1.47, 5.32; 8 studies, n=1110); NIR studies reported an increased risk (RR 3.23; CI 2.40, 4.24, 27 studies, n=4176); alpha agonist studies reported an increased but not statistically significant risk and only guanfacine was included (RR 1.49; CI 0.94, 2.37; 4 studies, n=919); p 0.005	D	Insufficient
KQ2 CER amphetamine vs methylphenidate	Appetite suppression	2 RCTs¹³¹^, ²³⁵	No systematic difference (RR 1.01; CI 0.72, 1.42; 3 comparisons, n=414)	I	Low for no difference
KQ2 CER NRI vs alpha agonists	Appetite suppression	1 RCT ³²⁶ (direct comparison), and N/A (indirect comparison)	A direct comparison showed more instances of appetite suppression with NRIs (RR 0.48; CI 0.27, 0.83; 1 study, n=226); in indirect comparisons NRI studies reported more instances of appetite suppression than alpha agonist studies (NRI RR 3.23; CI 2.40, 4.34; 27 studies, n=4176 vs alpha agonist RR 1.49; CI 0.94, 2.37; 4 studies; n=919; p 0.01)	D	Low for favoring alpha agonist studies
KQ2 CER non-stimulants vs stimulants	Participants with adverse events	N/A (indirect comparison)	No difference detected (p 0.12)	D	Low for no difference
KQ2 CER amphetamine vs methylphenidate vs NRI vs alpha agonist	Participants with adverse events	N/A (indirect comparison)	Amphetamine reported an increased risk (RR 1.41; CI 1.25, 1.58; 8 studies, n=1151); methylphenidate studies reported an increased risk (RR 1.32; CI 1.25, 1.40; 6 studies, n=945); NRI studies reported an increased risk (RR 1.31; CI 1.18, 1.46; 15 studies, n=2600); alpha agonist studies reported an increased risk (RR 1.21; CI 1.11, 1.31; 14 studies, n=2544); p 0.05	D	Insufficient
KQ2 CER NRIs vs stimulants	Participants with adverse events	4 RCTs¹⁷⁵^, ²²⁵^, ⁵³⁹^, ⁶⁰⁴	No difference detected (RR 1.11; CI 0.90, 1.37; 4 studies, n=756)	S	Low for no difference
KQ2 CER NRIs vs alpha agonists	Participants with adverse events	1 RCT ³²⁶ (direct comparison), N/A (indirect comparison)	No systematic difference (RR 1.14; CI 0.97, 1.34; 1 study, n=226) in a study comparing guanfacine and atomoxetine; indirect comparisons did also not detect an effect (p 0.06)	C	Low for no difference

: Notes: ADHD = attention deficit hyperactivity disorder, C = inconsistency, CER = Comparative Effectiveness Review, CI = 95% confidence interval, D indirectness, I imprecision, KQ = Key Question, N/A = not applicable, NRI = norepinephrine reuptake inhibitors, RCT = randomized controlled trial, RR = relative risk, S = study limitation, SMD = standardized mean differences, SoE = strength of evidence

From: 5, Results: Treatment of ADHD

Cover of ADHD Diagnosis and Treatment in Children and Adolescents

ADHD Diagnosis and Treatment in Children and Adolescents [Internet].

Comparative Effectiveness Review, No. 267.

Peterson BS, Trampush J, Maglione M, et al.

Rockville (MD): Agency for Healthcare Research and Quality (US); 2024 Mar.

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