Efficacy,Acceptability,and Tolerability of Lisdexamfetamine,Mixed Amphetamine Salts,Methylphenidate,and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis
Restricted accessResearch articleFirst published online February, 2019
Efficacy,Acceptability,and Tolerability of Lisdexamfetamine,Mixed Amphetamine Salts,Methylphenidate,and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis
Objective: Psychostimulants are the first-line treatment in adults with attention-deficit hyperactivity disorder (ADHD). This meta-analysis aimed to evaluate the efficacy, acceptability, and tolerability of lisdexamfetamine (LDX), mixed amphetamine salts (MASs), modafinil (MDF), and methylphenidate (MPH) in comparison with placebo. Data Sources: We systematically searched PubMed/MEDLINE and Clinicaltrials.gov in May 2016, along with CENTRAL and EU Clinical Trials Register in February 2016, for the randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted on adults diagnosed with ADHD. Study Selection and Data Extraction: Substantial comorbidity, substance abuse or dependence, and nonpharmacological interventions represented grounds for exclusion. Published reports were the sole source for data extraction. Improvement in ADHD symptoms was the primary outcome. Random-effects model meta-analysis was applied to calculate the standardized mean difference (SMD) with 95% CIs. Data Synthesis: The search retrieved 701 records, of which 20 studies were eligible for analysis. High effect size (expressed as SMD) in reducing ADHD symptoms was observed for LDX (−0.89; 95% CI = −1.09, −0.70), whereas MASs (−0.64; 95% CI = −0.83, −0.45) and MPH (−0.50; 95% CI = −0.58, −0.41) reduced symptoms moderately compared with placebo. No efficacy was shown for MDF (0.08; 95% CI; −0.18, 0.34). Relevance to Patient Care and Clinical Practice: In this meta-analysis, the efficacy, tolerability, and acceptability of psychostimulants were compared with that for placebo. Five of the included trials have not been evaluated in any of the previously published meta-analyses. Conclusions: The results suggest that LDX has the largest effect size and has a promising potential for treating adults with ADHD.
StuhecMMundaBSvabVLocatelliI.Comparative efficacy and acceptability of atomoxetine, lisdexamfetamine, bupropion and methylphenidate in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis with focus on bupropion. J Affect Disord. 2015;178:149-159. doi:10.1016/j.jad.2015.03.006
2.
PolanczykGVSalumGASugayaLSCayeARohdeLA.Annual research review: a meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. J Child Psychol Psychiatry. 2015;56:345-365. doi:10.1111/jcpp.12381
3.
ŠtuhecMŠvabVLocatelliI.Prevalence and incidence of attention-deficit/hyperactivity disorder in Slovenian children and adolescents: a database study from a national perspective. Croat Med J. 2015;56:159-165. doi:10.3325/cmj.2015.56.159
4.
BalintSCzoborPMeszarosASimonVBitterI.Neuropsychological impairments in adult attention deficit hyperactivity disorder: a literature review [in Hungarian]. Psychiatr Hung. 2008;23:324-335.
5.
DalsgaardSØstergaardSDLeckmanJFMortensenPBPedersenMG.Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet. 2015;385:2190-2196. doi:10.1016/S0140-6736(14)61684-6
6.
Bolea-AlamañacBNuttDJAdamouMet al; British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28:179-203. doi:10.1177/0269881113519509
7.
FaraoneSV.Using meta-analysis to compare the efficacy of medications for attention-deficit/hyperactivity disorder in youths. P T. 2009;34:678-694.
8.
FaraoneSVBiedermanJSpencerTJAleardiM.Comparing the efficacy of medications for ADHD using meta-analysis. MedGenMed. 2006;8:4.
9.
RoskellNSSetyawanJZimovetzEAHodgkinsP.Systematic evidence synthesis of treatments for ADHD in children and adolescents: indirect treatment comparisons of lisdexamfetamine with methylphenidate and atomoxetine. Curr Med Res Opin. 2014;30:1673-1685. doi:10.1185/03007995.2014.904772
10.
CastellsXRamos-QuirogaJABoschRNogueiraMCasasM.Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev. 2011;(6):CD007813. doi:10.1002/14651858.CD007813.pub2
11.
CastellsXRamos-QuirogaJARigauDet al. Efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder: a meta-regression analysis. CNS Drugs. 2011;25:157-169. doi:10.2165/11539440-000000000-00000
12.
CunillRCastellsXTobiasACapellàD.Efficacy, safety and variability in pharmacotherapy for adults with attention deficit hyperactivity disorder: a meta-analysis and meta-regression in over 9000 patients. Psychopharmacology (Berl). 2016;233:187-197. doi:10.1007/s00213-015-4099-3
13.
EpsteinTPatsopoulosNAWeiserM.Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev. 2014;(9):CD005041. doi:10.1002/14651858.CD005041.pub2
14.
FaraoneSV.Understanding the effect size of lisdexamfetamine dimesylate for treating ADHD in children and adults. J Atten Disord. 2012;16:128-137. doi:10.1177/1087054710379738
15.
FaraoneSVGlattSJ.A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry. 2010;71:754-763. doi:10.4088/JCP.08m04902pur
16.
FaraoneSVSpencerTAleardiMPaganoCBiedermanJ.Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2004;24:24-29. doi:10.1097/01.jcp.0000108984.11879.95
17.
KoestersMBeckerTKilianRFegertJMWeinmannS.Limits of meta-analysis: methylphenidate in the treatment of adult attention-deficit hyperactivity disorder. J Psychopharmacol. 2009;23:733-744. doi:10.1177/0269881108092338
18.
ManeetonNManeetonBSuttajitSReungyosJSrisurapanontMMartinSD.Exploratory meta-analysis on lisdexamfetamine versus placebo in adult ADHD. Drug Des Devel Ther. 2014;8:1685-1693. doi:10.2147/DDDT.S68393
19.
MészárosACzoborPBálintSKomlósiSSimonVBitterI.Pharmacotherapy of adult attention deficit hyperactivity disorder (ADHD): a meta-analysis. Int J Neuropsychopharmacol. 2009;12:1137-1147. doi:10.1017/S1461145709990198
20.
PetersonKMcDonaghMSFuR.Comparative benefits and harms of competing medications for adults with attention-deficit hyperactivity disorder: a systematic review and indirect comparison meta-analysis. Psychopharmacology (Berl). 2008;197:1-11. doi:10.1007/s00213-007-0996-4
21.
LiberatiAAltmanDGTetzlaffJet al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62:e1-e34. doi:10.1016/j.jclinepi.2009.06.006
22.
HigginsJPTGreenS, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. London, England: Cochrane Collaboration; 2011. http://handbook-5-1.cochrane.org/. Accessed August 6, 2018.
23.
SpencerTJAdlerLAWeislerRHYouchaSH.Triple-bead mixed amphetamine salts (SPD465), a novel, enhanced extended-release amphetamine formulation for the treatment of adults with ADHD: a randomized, double-blind, multicenter, placebo-controlled study. J Clin Psychiatry. 2008;69:1437-1448. doi:10.4088/JCP.v69n0911
24.
WeislerRHBiedermanJSpencerTJet al. Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized, controlled trial. CNS Spectr. 2006;11:625-639.
25.
AdlerLGoodmanDWKollinsSHet al; 303 Study Group. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69:1364-1373. doi:10.4088/JCP.v69n0903
26.
AdlerLADirksBDeasPFet al. Lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder who report clinically significant impairment in executive function: results from a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74:694-702. doi:10.4088/JCP.12m08144
27.
BiedermanJFriedRHammernessPet al. The effects of lisdexamfetamine dimesylate on the driving performance of young adults with ADHD: a randomized, double-blind, placebo-controlled study using a validated driving simulator paradigm. J Psychiatr Res. 2012;46:484-491. doi:10.1016/j.jpsychires.2012.01.007
28.
AdlerLAZimmermanBStarrHLet al. Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2009;29:239-247. doi:10.1097/JCP.0b013e3181a390ce
29.
BiedermanJMickESurmanCet al. A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2006;59:829-835. doi:10.1016/j.biopsych.2005.09.011
30.
BiedermanJMickESurmanCet al. A randomized, 3-phase, 34-week, double-blind, long-term efficacy study of osmotic-release oral system-methylphenidate in adults with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2010;30:549-553. doi:10.1097/JCP.0b013e3181ee84a7
31.
CasasMRöslerMKooijSJJet al. Efficacy and safety of prolonged-release OROS methylphenidate in adults with attention deficit/hyperactivity disorder: a 13-week, randomized, double-blind, placebo-controlled, fixed-dose study. World J Biol Psychiatry. 2013;14:268-281. doi:10.3109/15622975.2011.600333
32.
GoodmanDWStarrHLMaY-WRostainALAscherSArmstrongRB.Randomized, 6-week, placebo-controlled study of treatment for adult attention-deficit/hyperactivity disorder: individualized dosing of osmotic-release oral system (OROS) methylphenidate with a goal of symptom remission. J Clin Psychiatry. 2017;78:105-114. doi:10.4088/JCP.15m10348
33.
HussMGinsbergYTvedtenTet al. Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Adv Ther. 2014;31:44-65. doi:10.1007/s12325-013-0085-5
34.
KupermanSPerryPJGaffneyGRet al. Bupropion SR vs methylphenidate vs placebo for attention deficit hyperactivity disorder in adults. Ann Clin Psychiatry. 2001;13:129-134. doi:10.1023/A:1012239823148
35.
MedoriRRamos-QuirogaJACasasMet al. A randomized, placebo-controlled trial of three fixed dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2008;63:981-989. doi:10.1016/j.biopsych.2007.11.008
36.
RetzWRöslerMOseCet al. Multiscale assessment of treatment efficacy in adults with ADHD: a randomized placebo-controlled, multi-centre study with extended-release methylphenidate. World J Biol Psychiatry. 2012;13:48-59. doi:10.3109/15622975.2010.540257
37.
RöslerMFischerRAmmerROseCRetzW.A randomised, placebo-controlled, 24-week, study of low-dose extended-release methylphenidate in adults with attention-deficit/hyperactivity disorder. Eur Arch Psychiatry Clin Neurosci. 2009;259:120-129. doi:10.1007/s00406-008-0845-4
38.
SpencerTBiedermanJWilensTet al. A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57:456-463. doi:10.1016/j.biopsych.2004.11.043
39.
SpencerTJAdlerLAMcGoughJJMunizRJiangHPestreichL; Adult ADHD Research Group. Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61:1380-1387. doi:10.1016/j.biopsych.2006.07.032
40.
TakahashiNKohTTominagaYSaitoYKashimotoYMatsumuraT.A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of osmotic-controlled release oral delivery system methylphenidate HCl in adults with attention-deficit/hyperactivity disorder in Japan. World J Biol Psychiatry. 2014;15:488-498. doi:10.3109/15622975.2013.868925
41.
WeislerRHPandinaGJDalyEJCooperKGassmann-MayerC; 31001074-ATT2001 Study Investigators. Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder. CNS Drugs. 2012;26:421-434. doi:10.2165/11631990-000000000-00000
42.
ArnoldVKFeifelDEarlCQYangRAdlerLA.A 9-week, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study to evaluate the efficacy and safety of modafinil as treatment for adults with ADHD. J Atten Disord. 2014;18:133-144. doi:10.1177/1087054712441969
43.
BiedermanJMickEFriedRWilnerNSpencerTJFaraoneSV.Are stimulants effective in the treatment of executive function deficits? Results from a randomized double blind study of OROS-methylphenidate in adults with ADHD. Eur Neuropsychopharmacol. 2011;21:508-515. doi:10.1016/j.euroneuro.2010.11.005
44.
BanaschewskiTCoghillDSantoshPet al. Long-acting medications for the hyperkinetic disorders: a systematic review and European treatment guideline. Eur Child Adolesc Psychiatry. 2006;15:476-495. doi:10.1007/s00787-006-0549-0
45.
RetzWRetz-JungingerPThomeJRöslerM.Pharmacological treatment of adult ADHD in Europe. World J Biol Psychiatry. 2011;12(suppl 1):89-94. doi:10.3109/15622975.2011.603229
46.
StuhecMLocatelliI.Age-related pharmacotherapy of attention deficit hyperactivity disorder in Slovenia in children and adolescents: a population-based study. Eur Psychiatry. 2017;42:129-133. doi:10.1016/j.eurpsy.2017.01.002
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
