TY - JOUR
T1 - Does l-Methylfolate Supplement Methylphenidate Pharmacotherapy in Attention-Deficit/Hyperactivity Disorder?
T2 - Evidence of Lack of Benefit from a Double-Blind, Placebo-Controlled, Randomized Clinical Trial
AU - Surman, Craig
AU - Ceranoglu, Atilla
AU - Vaudreuil, Carrie
AU - Albright, Brittany
AU - Uchida, Mai
AU - Yule, Amy
AU - Spencer, Andrea
AU - Boland, Heidi
AU - Grossman, Rebecca
AU - Rhodewalt, Lauren
AU - Fitzgerald, Maura
AU - Biederman, Joseph
N1 - Funding Information:
Pamlab Inc, supported this research project. C.S. has received, in his lifetime, consulting fees from McNeil, NLS, Nutricia, Pfizer, Rhodes, Shire, Somaxon, Sunovion, and Takeda. He has also received payments for lectures for Alcobra, McNeil, Janssen, Janssen-Ortho, Novartis, Shire, and Reed/MGH Academy, as well as GME CME (both funded by multiple companies). Royalties have been given to C.S. from Berkeley/Penguin for "FASTMINDS How to Thrive if You Have ADHD (or Think You Might)" and from Humana/Springer for "ADHD in Adults: A Practical Guide to Evaluation and Management". Additionally, C.S. has conducted clinical research at Massachusetts General Hospital (MGH) supported by Abbot, Cephalon, Hilda and Preston Davis Foundation, Eli Lilly, Magceutics/Neurocentria, Johnson & Johnson/McNeil, Lundbeck, Merck, and Nordic Naturals. A.C.: employment/ salary: MGH, private practice; coinvestigator on studies funded by Pamlab Inc, Sunovion Pharmaceuticals Inc, Lundbeck A/S, Pfizer Inc, NIH, Magceutics Inc, Department of Defense, AACAP, and MGH Department of Psychiatry. C.V., B.A., M.U., H.B., M.F., L.R., and A.S. declare no conflicts of interest. A.Y. received grant support from the American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC, in 2012. She received grant support from the MGH Louis V. Gerstner III Research Scholar Award from 2014 to 2016. A.Y. is currently receiving funding through the American Academy of Child and Adolescent Psychiatry Physician Scientist Program in Substance Abuse 5K12DA000357-17. She is a consultant to Phoenix House (clinical service). J.B. is receiving research support from the following sources: AACAP, The Department of Defense, Food & Drug Administration, Headspace, Lundbeck, Neurocentria Inc., NIDA, PamLab, Pfizer, Shire Pharmaceuticals Inc, Sunovion, and NIH. J.B. has a financial interest in Avekshan LLC, a company that develops treatments for ADHD. His interests were reviewed and are managed by MGH and Partners HealthCare in accordance with their conflict of interest policies. J.B.'s program has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Ingenix, Prophase, Shire, Bracket Global, Sunovion, and Theravance; these royalties were paid to the Department of Psychiatry at MGH. In 2017, J.B. is a consultant to Aevi Genomics, Akili, Guidepoint, Ironshore, Medgenics, and Piper Jaffray. He is on the scientific advisory board for Alcobra and Shire. He received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses. Through MGH corporate licensing, he has a US patent (#14/ 027,676) for a nonstimulant treatment for ADHD and a patent pending (#61/233,686) on a method to prevent stimulant abuse. In 2016, J.B. received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses and from Alcobra and APSARD. He was on the scientific advisory board for Arbor Pharmaceuticals. He was a consultant to Akili and Medgenics. He received research support from Merck and SPRITES. In 2015, J.B. received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses and from Avekshan. He received research support from Ironshore, Magceutics Inc, and Vaya Pharma/Enzymotec. In 2014, J.B. received honoraria from the MGH Psychiatry Academy for tuition-funded CME courses. He received research support from AACAP, Alcobra, Forest Research Institute, and Shire Pharmaceuticals Inc. In previous years, J.B. received research support, consultation fees, or speaker's fees for/from the following additional sources: Abbott, Alza, APSARD, AstraZeneca, Boston University, Bristol-Myers Squibb, Cambridge University Press, Celltech, Cephalon, The Children's Hospital of Southwest Florida/Lee Memorial Health System, Cipher Pharmaceuticals Inc, Eli Lilly and Co, Esai, ElMindA, Fundacion Areces (Spain), Forest, Fundación Dr Manuel Camelo A.C., Glaxo, Gliatech, Hastings Center, Janssen, Juste Pharmaceutical Spain, McNeil, Medice Pharmaceuticals (Germany), Merck, MGH Psychiatry Academy, MMC Pediatric, NARSAD, NIDA, New River, NICHD, NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, Phase V Communications, Physicians Academy, The Prechter Foundation, Quantia Communications, Reed Exhibitions, Shionogi Pharma Inc, Shire, the Spanish Child Psychiatry Association, The Stanley Foundation, UCB Pharma Inc, Veritas, and Wyeth.
Publisher Copyright:
© Wolters Kluwer Health, Inc. All rights reserved.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Purpose/Background Interventions for attention-deficit/hyperactivity disorder (ADHD) may be inadequate for some patients. There is evidence that supplementation with l-methylfolate augments antidepressant agent effects and thus might also augment ADHD treatment effects by a common catecholaminergic mechanism. Methods Forty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of ADHD participated in a randomized, double-blind, placebo-controlled, 12-week trial of 15 mg of l-methylfolate in combination with osmotic-release oral system methylphenidate. Osmotic-release oral system methylphenidate was dose optimized over the first 6 weeks. We evaluated the effects on ADHD symptoms, self-report on the Behavior Rating Inventory of Executive Function of executive function, methylphenidate dosing, neuropsychological test measures, the Adult ADHD Self-report scale, emotional dysregulation, social adjustment, and work productivity, as well as moderating effects of body mass index, autoantibodies to folate receptors, and select genetic polymorphisms. Results l-Methylfolate was well tolerated, with no significant effect over placebo except improvement from abnormal measures on the mean adaptive dimension of the ASR scale (χ 2 = 4.36, P = 0.04). Methylphenidate dosing was significantly higher in individuals on l-methylfolate over time (χ 2 = 7.35, P = 0.007). Exploratory analyses suggested that variation in a guanosine triphosphate cyclohydrolase gene predicted association with higher doses of methylphenidate (P < 0.001). Conclusions l-Methylfolate was associated with no change in efficacy on measures relevant to neuropsychiatric function in adults with ADHD, other than suggestion of reduced efficacy of methylphenidate. Further investigation would be required to confirm this effect and its mechanism and the genotype prediction of effects on dosing.
AB - Purpose/Background Interventions for attention-deficit/hyperactivity disorder (ADHD) may be inadequate for some patients. There is evidence that supplementation with l-methylfolate augments antidepressant agent effects and thus might also augment ADHD treatment effects by a common catecholaminergic mechanism. Methods Forty-four adults with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of ADHD participated in a randomized, double-blind, placebo-controlled, 12-week trial of 15 mg of l-methylfolate in combination with osmotic-release oral system methylphenidate. Osmotic-release oral system methylphenidate was dose optimized over the first 6 weeks. We evaluated the effects on ADHD symptoms, self-report on the Behavior Rating Inventory of Executive Function of executive function, methylphenidate dosing, neuropsychological test measures, the Adult ADHD Self-report scale, emotional dysregulation, social adjustment, and work productivity, as well as moderating effects of body mass index, autoantibodies to folate receptors, and select genetic polymorphisms. Results l-Methylfolate was well tolerated, with no significant effect over placebo except improvement from abnormal measures on the mean adaptive dimension of the ASR scale (χ 2 = 4.36, P = 0.04). Methylphenidate dosing was significantly higher in individuals on l-methylfolate over time (χ 2 = 7.35, P = 0.007). Exploratory analyses suggested that variation in a guanosine triphosphate cyclohydrolase gene predicted association with higher doses of methylphenidate (P < 0.001). Conclusions l-Methylfolate was associated with no change in efficacy on measures relevant to neuropsychiatric function in adults with ADHD, other than suggestion of reduced efficacy of methylphenidate. Further investigation would be required to confirm this effect and its mechanism and the genotype prediction of effects on dosing.
KW - attention-deficit/hyperactivity disorder
KW - l-methylfolate
KW - medical food
KW - methylphenidate
UR - http://www.scopus.com/inward/record.url?scp=85058895401&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058895401&partnerID=8YFLogxK
U2 - 10.1097/JCP.0000000000000990
DO - 10.1097/JCP.0000000000000990
M3 - Article
C2 - 30566416
AN - SCOPUS:85058895401
SN - 0271-0749
VL - 39
SP - 28
EP - 38
JO - Journal of clinical psychopharmacology
JF - Journal of clinical psychopharmacology
IS - 1
ER -
