Beyond stimulants: a systematic review of randomised controlled trials assessing novel compounds for ADHD

ABSTRACT

Introduction: Despite stimulants being highly efficacious in short-term randomized controlled trials (RCTs), not all patients respond or can successfully tolerate them. A number of novel non-stimulant options are currently in the pipeline for the treatment of attention-deficit/hyperactivity disorder (ADHD).

Areas covered: The authors conducted a systematic review of RCTs registered in ClinicalTrials.gov in the past 5 years (January 2014 and February 2019), supplemented by searches in PubMed, Web of Science, and drug manufacturer websites to find recent RCTs on novel non-stimulant ADHD medications.

Expert opinion: The authors found 28 pertinent RCTs of compounds acting on a variety of biological targets, including Dasotraline, Viloxazine (SPN-812), Centanafadine SR (CTN SR), OPC-64005, Fasoracetam (NFC-1, AEVI-001), Metadoxine (MDX), Vortioxetine, Tipepidine Hibenzate, Oxytocin, Sativex (delta-9-tetrahydrocannabinol (THC) plus cannabidiol), Mazindol, and Molindone hydrochloride (SPN-810). Given the high effect size found in RCTs of stimulants in terms of efficacy on ADHD core symptoms, it is unlikely that these novel agents will show better efficacy than stimulants, at the group level. However, they may offer comparable or better tolerability. Additionally, agents acting on etiopathophysiological targets disrupted in specific subgroups of patients with ADHD will move forward the pharmacotherapy of ADHD from a ‘one size fits all’ to a ‘precision medicine’ approach.

KEYWORDS:

• ADHD
• medication
• stimulants
• non-stimulants
• druggable genome

Article highlights

• Stimulants, including methylphenidate and amphetamines, are the mainstay of pharmacological treatment for ADHD

• Although stimulants are highly efficacious at the group level, a sizable portion of patients with ADHD do not respond to them or cannot tolerate them

• Our systematic review of trials registered in ClinicalTrials.gov in the past 5 years showed that a number of compounds other than methylphenidate or amphetamines are being tested for the core symptoms of ADHD

• For a number of these studies, peer-reviewed results have not been published

Declaration of interest

S Cortese has received reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH), a non-profit organisation, in relation to lectures that he delivered for ACAMH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has received grant support from the U.S. Food & Drug Administrationas well as research support from: Noven, Shire, Lundbeck, Pearson, Alcobra, Akili, Arbor, Eli Lilly, Ironshore, Forest Laboratories, Aevi Genomic Medicine, Neos Therapeutics, Neurovance, Otsuka America Pharmaceutical, Pfizer, Purdue, Rhodes, Sunovion, Tris, KenPharm and Supernus. They have also received writing support from: Shire, Ironshore, Neos Therapeutics, Pfizer, Rhodes and Tris. They have also served on advisory boards for: Noven, Akili, Arbor, Cingulate, Ironshore, Neos Therapeutics, Neurovance, Pfizer, Purdue, Rhodes, Sunovion, Tris and Supernus. They have also acted as a consultant to Shire, Akili, Arbor, Ironshore, Neos Therapeutics, Neurovance, Purdue, Rhodes, Sunovion, Tris, KemPharm and Supernus. They have acted on the speakers’ bureau for Shire and Pfizer and have received speaker fees from Arbor. Finally, they have received travel support from Ironshore. Another reviewer on this manuscript has received research support, acted on the advisory board of and as a consultant to: Akili, Cingulate Therapeutics, Ironshore Pharma, NuTec, NueroLife Sciences, Otsuka, Ofizer, Purdue, Rho, Rhodes, Shire, Sunovion, Touchpoint and Tris. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.