Abstract
Introduction
Attention-deficit hyperactivity disorder (ADHD), the most common neurodevelopmental disorder, with a prevalence of 6–7% in children, stands at the intersection of neurological complexity and individual experience and still presents a myriad of challenges and opportunities for understanding and interventions. 1 Keeping in view the diverse and dynamic nature of ADHD, the quest for effective interventions has given rise to a wave of innovative treatment options.
Background
Stimulant medications (amphetamines & methylphenidate) and non-stimulant medication (atomoxetine) have remained the mainstay of treatment for ADHD. Although amphetamines were first synthesized as early as 1887, they were not studied clinically until 1927, first as an artificial replacement for epinephrine and later for many years as a bronchodilator. In 1937, effects of Benzedrine sulfate administered for headaches to 30 children aged 5–14 years were observed for a range of behavioral problems. But it was not until the 1950s that research in stimulant medications became, in a true sense, relevant to ADHD; by this time, methylphenidate (MPH), an amphetamine derivative, was synthesized in 1944 and subsequently marketed as ‘ritalin’.2,3 This was followed by a surge in studies of the treatment of children with ADHD (then hyperkinetic reactions of childhood in DSM-II & attention deficit disorder in DSM-III) by stimulants.
Currently, stimulant medications remain the most common FDA-approved treatment for ADHD, with a diverse array of delivery mechanisms being developed, including longer-acting compound preparations. Alternative FDA-approved drugs include norepinephrine reuptake inhibitors (atomoxetine) and alpha-adrenergic agonists (Guanfacine & Clonidine). There is adequate literature confirming the effectiveness of pharmacotherapy in ADHD, with effect sizes ranging from 0.9–1.1 for amphetamines, 0.64-0.91 for methylphenidate, 0.52–0.82 for atomoxetine and ~0.5 for clonidine and guanfacine.4,5 A range of adverse effects are documented with ADHD medications, with most adverse effects being transient and dose-dependent, though appetite loss as a side effect may persist for years. 6 Additionally, stimulants are classified as Schedule II drugs as they have ‘a high potential for abuse’ and carry the risk of diversion (unlawful transfer of prescription medication from their licit medical purpose to the illicit marketplace), which is now becoming an increasingly prevalent problem. 7
Recent Advances
Pharmacotherapy
In the recent few years, many new stimulant preparations with a potential advantage over the traditional preparations have been marketed following regulatory approval.
Lisdexamfetamine dimesylate (LDX; Vyvanse) is the first chemically formulated prodrug (in vivo conversion of LDX to d-amphetamine), which is also a long-acting stimulant for ADHD, approved by FDA in 2007 and in 2008 for use in adults with ADHD. The in-vivo conversion of LDX to d-amphetamine is facilitated by enzymatic hydrolysis leading to production of l-lysine, a naturally occurring amino acid as a by-product. 8 The advantages of LDX includes: once-daily dosing, leading to a long-term effect throughout the day; gastrointestinal transit time having an unlikely impact on the availability of active drugs; reduced risk of pH-mediated food or drug interactions (which makes it relevant for use in adults with ADHD who often take over-the-counter drugs that alter gastric pH); and a possible lower potential for abuse or diversion. LDX has shown low inter-patient variability in pharmacokinetic properties, which may be due to the absence of a mechanized delivery system. Another significant advantage, especially for children, is that the capsules may be opened and their entire contents dissolved in a glass of water, thus making it easier to swallow compared to any other capsule/tablet and also making it the first and only liquid long-acting stimulant. 8 The dose range varies from 30 mg/day to 70mg/day with the effect lasting for ~ 13–14 hours. Decreased appetite, dry mouth, irritability, insomnia, nausea, upper abdominal pain and decreased weight are the reported side effects. Overall, it is reported that LDX use is associated with lower daily average consumption, a lesser need for augmentation and, thus, increased adherence to treatment. 8
More recently, the FDA has approved several first generics for LDX, following which drug makers in the US, UK and India have sprung into action to ship their generic versions of the drug. Generic drugs will offer more options for patients and should potentially also help lower prices. How long it takes for a generic version to be available in India and what it will cost will have to be seen.
A delayed-release or extended-release methylphenidate hydrochloride (Jornay PM) has been marketed since 2019 following FDA approval in 2018. The peculiar difference between this preparation and other methylphenidate-based stimulants is that it is administered ‘before bedtime’, between 6:30
A combination of serdexmethylphenidate (SDX; an extended duration prodrug of dexmethylphenidate) and dexmethylphenidate (d-MPH) in a 70/30 molar ratio, classified as the Schedule IV drug by the US Drug Enforcement Administration (DEA), may be of benefit to subjects with an increased risk of abuse. 7
Patches of transdermal dextroamphetamines (at doses of 4.5 mg, 9 mg, 13.5 mg, and 18 mg) versus placebo have been tested in a phase 2 randomized, placebo-controlled trial and proven beneficial in improving ADHD symptoms measured on the SKAMP (Swanson, Kotkin, Agler, M-Flynn, & Pelham) rating scale. Drug delivery through patches offers the advantage of addressing drug adherence issues, monitoring, reducing dosing frequency, and reducing drug-drug interactions. 11,12
Viloxazine ER (VER) is a recently approved non- stimulant drug for the treatment of ADHD in children aged 6–17 years. It belongs to the selective nor-epinephrine reuptake inhibitor class with agonist activity at several postsynaptic 5-HT receptors. Like atomoxetine, it carries the black box warning about an increase in suicidality in the initial months of treatment, especially in adolescents; however, despite the warning, treatment benefits outweigh the risks. Children with ADHD randomized to groups receiving 100 mg/day and 200 mg/day of VER showed improvement after 2 weeks in a phase 3 clinical trial. 13 These findings corroborate findings from another phase 3 clinical trial of VER in adults with ADHD randomized to receive doses between 200 mg/day and 600 mg/day. 14 VER is sold by the trade name ‘Qelbree’ as 100 mg, 150 mg, and 200 mg capsules and can be made available to patients, doctors, and hospitals in many cities of India on a prescription.
Another non-stimulant drug under investigation in a late-stage clinical trial is centanafadine. 15 It is a novel reuptake inhibitor of serotonin, norepinephrine, and dopamine and thus has potential use in the treatment of ADHD.
Digital Therapeutics
Recently, two devices have been approved by the FDA for the treatment of ADHD. Here, it is important to remember that the standard for FDA approval for devices is lower than that for drugs; devices need only prove safety, whereas drugs must prove both safety and efficacy. The best utilization of these devices remains to be determined. However, these do have merit in augmenting the response in individuals with ADHD who are not showing an adequate response to pharmacotherapy and even as an alternative to medications. 7
The Monarch external Trigeminal Nerve Stimulation (eTNS) system is a trigeminal nerve stimulator already being used in Europe and Canada, after US-FDA approval in 2019. It is placed on the face and does not require surgical insertion, unlike the vagal nerve stimulator used for controlling seizures. Users of this system need to wear a patch across the forehead at night, which facilitates delivering an electrical signal to brain areas associated with concentration and impulse control. 16
EndeavorRx is a video game approved by FDA in 2020 for augmenting the treatment of ADHD in children aged 8–12 years. The sensory stimuli and motor challenges of the game target the neural pathways that govern focus and attention. 17
Conclusions
Although the stimulant medications with the most evidence for ADHD are methylphenidate, dexamphetamine, and lisdexamfetamine, methylphenidate is the only stimulant available in India 19 . Among the non-stimulants, atomoxetine and clonidine are available and used commonly in India. 19 Modafinil and bupropion are considered third-line drugs. 19 Hence, it can be seen that for management of ADHD in India, there is a desperate need for the introduction of newer medications and devices to help children with ADHD and their families.
There are ongoing research efforts to gain a deeper understanding of the neurobiology and neurogenetics of ADHD. Consequently, efforts are being made to find biological markers, including pharmacogenomic markers for ADHD which have the potential to inform treatment response, adverse effects and allow for therapeutic drug monitoring. Age and gender specific differences with regard to pharmacotherapeutics is still an under-researched area and requires further research for a better understanding. Further research into the use of neuromodulation techniques, that is, rTMS (repetitive transcranial magnetic stimulation) and tDCS (transcranial direct current stimulation) with larger sample sizes and standardized outcome measures may prove their benefit for the treatment of ADHD 18 . While individuals with ADHD still face numerous unmet needs, the armamentarium for therapeutic care is continually expanding; we all—professionals, patients and caregivers—wait with bated breath, but with ‘hope’.
Footnotes
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Disclaimer
This editorial expresses the opinion exclusively of the authors, and not necessarily of the Journal.
Funding
The authors received no financial support for the research, authorship and/or publication of this article.