Combined Stimulant and Guanfacine Administration in Attention-Deficit/Hyperactivity Disorder: A Controlled, Comparative Study

Overview

Journal J Am Acad Child Adolesc Psychiatry

Publisher Elsevier

Specialties Pediatrics
Psychiatry

Date 2016 Jul 26

PMID 27453079

Citations 23

Authors

James T McCracken

James J McGough

Sandra K Loo

Jennifer Levitt

Melissa DelHomme

Jennifer Cowen

Alexandra Sturm

Fiona Whelan

Gerhard Hellemann

Catherine Sugar

Robert M Bilder

Affiliations

Soon will be listed here.

Abstract

Objective: Because models of attention-deficit/hyperactivity disorder (ADHD) therapeutics emphasize benefits of both enhanced dopaminergic and noradrenergic signaling, strategies to enhance D1 and α2A agonism may yield enhanced clinical and cognitive responses. This study tested the hypothesis that combined effects of a dopamine and noradrenergic agonist, d-methylphenidate extended-release (DMPH) with guanfacine (GUAN), an α2A receptor agonist, would be clinically superior to either monotherapy and would have equal tolerability.

Method: An 8-week, double-blind, 3-arm, comparative trial randomized 7- to 14-year-olds with DSM-IV ADHD to GUAN (1-3 mg/day), DMPH (5-20 mg/day), or a combination (COMB) with fixed-flexible dosing. Outcome measures were the ADHD Rating Scale IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Data on adverse events and safety measures were obtained.

Results: A total of 207 participants were randomized and received drug. Analyses showed significant treatment group main effects for ADHD-RS-IV ADHD total (p = .0001) and inattentive symptoms (p = .0001). COMB demonstrated small but consistently greater reductions in ADHD-RS-IV Inattentive subscale scores versus monotherapies (DMPH: p = .05; f(2) = .02; and GUAN: p = .02; f(2) = .02), and was associated with a greater positive response rate by CGI-I (p = .01). No serious cardiovascular events occurred. Sedation, somnolence, lethargy, and fatigue were greater in both guanfacine groups. All treatments were well tolerated.

Conclusion: COMB showed consistent evidence of clinical benefits over monotherapies, possibly reflecting advantages of greater combined dopaminergic and α2A agonism. Adverse events were generally mild to moderate, and COMB treatment showed no differences in safety or tolerability.

Clinical Trial Registration Information: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); http://clinicaltrials.gov/; NCT00429273.

Citing Articles

Translating Decades of Neuroscience Research into Diagnostic and Treatment Biomarkers for ADHD.

Loo S, Lenartowicz A, Norman L, Michelini G Adv Neurobiol. 2024; 40:579-616.

PMID: 39562458 DOI: 10.1007/978-3-031-69491-2_20.

Case Report: Guanfacine and methylphenidate improved chronic lower back pain in autosomal dominant polycystic kidney disease with comorbid attention deficit hyperactivity disorder and autism spectrum disorder.

Kasahara S, Kanda S, Takahashi M, Fujioka M, Morita T, Matsudaira K Front Pediatr. 2023; 11:1283823.

PMID: 38027301 PMC: 10646415. DOI: 10.3389/fped.2023.1283823.

Adrenoceptors: A Focus on Psychiatric Disorders and Their Treatments.

Stanford S, Heal D Handb Exp Pharmacol. 2023; 285:507-554.

PMID: 37495853 DOI: 10.1007/164_2023_675.

The Role of Alpha-2 Agonists for Attention Deficit Hyperactivity Disorder in Children: A Review.

Neuchat E, Bocklud B, Kingsley K, Barham W, Luther P, Ahmadzadeh S Neurol Int. 2023; 15(2):697-707.

PMID: 37218982 PMC: 10204383. DOI: 10.3390/neurolint15020043.

Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).

Storebo O, Storm M, Ribeiro J, Skoog M, Groth C, Callesen H Cochrane Database Syst Rev. 2023; 3:CD009885.

PMID: 36971690 PMC: 10042435. DOI: 10.1002/14651858.CD009885.pub3.

References

Daviss W, Patel N, Robb A, McDermott M, Bukstein O, Pelham Jr W . Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis. J Am Acad Child Adolesc Psychiatry. 2008; 47(2):189-198. DOI: 10.1097/chi.0b013e31815d9ae4. View

Vijayraghavan S, Wang M, Birnbaum S, Williams G, Arnsten A . Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci. 2007; 10(3):376-84. DOI: 10.1038/nn1846. View

Kaufman J, Birmaher B, Brent D, Ryan N, Rao U . K-SADS-PL. J Am Acad Child Adolesc Psychiatry. 2000; 39(10):1208. DOI: 10.1097/00004583-200010000-00002. View

Levy F . Dopamine vs noradrenaline: inverted-U effects and ADHD theories. Aust N Z J Psychiatry. 2009; 43(2):101-8. DOI: 10.1080/00048670802607238. View

Arnsten A, Pliszka S . Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders. Pharmacol Biochem Behav. 2011; 99(2):211-6. PMC: 3129015. DOI: 10.1016/j.pbb.2011.01.020. View

Halperin J, Trampush J, Miller C, Marks D, Newcorn J . Neuropsychological outcome in adolescents/young adults with childhood ADHD: profiles of persisters, remitters and controls. J Child Psychol Psychiatry. 2008; 49(9):958-66. PMC: 2646044. DOI: 10.1111/j.1469-7610.2008.01926.x. View

Gadow K . Effects of stimulant drugs on academic performance in hyperactive and learning disabled children. J Learn Disabil. 1983; 16(5):290-9. DOI: 10.1177/002221948301600509. View

Steele M, Jensen P, Quinn D . Remission versus response as the goal of therapy in ADHD: a new standard for the field?. Clin Ther. 2007; 28(11):1892-908. DOI: 10.1016/j.clinthera.2006.11.006. View

Swanson J, Kraemer H, Hinshaw S, Arnold L, Conners C, Abikoff H . Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment. J Am Acad Child Adolesc Psychiatry. 2001; 40(2):168-79. DOI: 10.1097/00004583-200102000-00011. View

10.

Biederman J, Melmed R, Patel A, McBurnett K, Konow J, Lyne A . A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2008; 121(1):e73-84. DOI: 10.1542/peds.2006-3695. View

11.

McGough J, Pataki C, Suddath R . Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder. Expert Rev Neurother. 2005; 5(4):437-41. DOI: 10.1586/14737175.5.4.437. View

12.

Hechtman L, Abikoff H, Klein R, Weiss G, Respitz C, Kouri J . Academic achievement and emotional status of children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment. J Am Acad Child Adolesc Psychiatry. 2004; 43(7):812-9. DOI: 10.1097/01.chi.0000128796.84202.eb. View

13.

Scheffler R, Brown T, Fulton B, Hinshaw S, Levine P, Stone S . Positive association between attention-deficit/ hyperactivity disorder medication use and academic achievement during elementary school. Pediatrics. 2009; 123(5):1273-9. DOI: 10.1542/peds.2008-1597. View

14.

. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999; 56(12):1073-86. DOI: 10.1001/archpsyc.56.12.1073. View

15.

Biederman J, Monuteaux M, Doyle A, Seidman L, Wilens T, Ferrero F . Impact of executive function deficits and attention-deficit/hyperactivity disorder (ADHD) on academic outcomes in children. J Consult Clin Psychol. 2004; 72(5):757-66. DOI: 10.1037/0022-006X.72.5.757. View

16.

Rapport M, Denney C, DuPaul G, Gardner M . Attention deficit disorder and methylphenidate: normalization rates, clinical effectiveness, and response prediction in 76 children. J Am Acad Child Adolesc Psychiatry. 1994; 33(6):882-93. DOI: 10.1097/00004583-199407000-00015. View

17.

Castellanos F . Toward a pathophysiology of attention-deficit/hyperactivity disorder. Clin Pediatr (Phila). 1997; 36(7):381-93. DOI: 10.1177/000992289703600702. View

18.

Elia J, Borcherding B, Rapoport J, Keysor C . Methylphenidate and dextroamphetamine treatments of hyperactivity: are there true nonresponders?. Psychiatry Res. 1991; 36(2):141-55. DOI: 10.1016/0165-1781(91)90126-a. View

19.

Abikoff H, Hechtman L, Klein R, Gallagher R, Fleiss K, Etcovitch J . Social functioning in children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment. J Am Acad Child Adolesc Psychiatry. 2004; 43(7):820-9. DOI: 10.1097/01.chi.0000128797.91601.1a. View

20.

Willcutt E, Doyle A, Nigg J, Faraone S, Pennington B . Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry. 2005; 57(11):1336-46. DOI: 10.1016/j.biopsych.2005.02.006. View