Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents

Abstract

Attention-deficit/hyperactivity disorder (ADHD), the single most common neuropsychiatric disorder with cognitive and behavioral manifestations, often starts in childhood and usually persists into adolescence and adulthood. Rarely seen alone, ADHD is most commonly complicated by other neuropsychiatric disorders that must be factored into any intervention plan to optimally address ADHD symptoms. With more than 30 classical Schedule II (CII) stimulant preparations available for ADHD treatment, only three nonstimulants (atomoxetine and extended-release formulations of clonidine and guanfacine) have been approved by the United States Food and Drug Administration (FDA), all of which focus on modulating the noradrenergic system. Given the heterogeneity and complex nature of ADHD in most patients, research efforts are identifying nonstimulants which modulate pathways beyond the noradrenergic system. New ADHD medications in clinical development include monoamine reuptake inhibitors, monoamine receptor modulators, and multimodal agents that combine receptor agonist/antagonist activity (receptor modulation) and monoamine transporter inhibition. Each of these “pipeline” ADHD medications has a unique chemical structure and differs in its pharmacologic profile in terms of molecular targets and mechanisms. The clinical role for each of these agents will need to be explored with regard to their potential to address the heterogeneity of individuals struggling with ADHD and ADHD-associated comorbidities. This review profiles alternatives to Schedule II (CII) stimulants that are in clinical stages of development (Phase 2 or 3). Particular attention is given to viloxazine extended-release, which has completed Phase 3 studies in children and adolescents with ADHD.

The Effect of Viloxazine Extended-Release Capsules on Functional Impairments Associated with Attention-Deficit/Hyperactivity Disorder (ADHD) in Children and Adolescents in Four Phase 3 Placebo-Controlled Trials

“… 1 Although multiple stimulant and nonstimulant treatment options have demonstrated efficacy in the treatment of ADHD, there is a significant proportion of individuals with ADHD who do not or only partially benefit from these medications and/or have contraindications, tolerability, or preference issues. 2 , 3 …”

“…1 Although multiple stimulant and nonstimulant treatment options have demonstrated efficacy in the treatment of ADHD, there is a significant proportion of individuals with ADHD who do not or only partially benefit from these medications and/or have contraindications, tolerability, or preference issues. 2,3 Historically, the assessment of treatment response in individuals with ADHD has focused on measures of ADHD symptoms. However, functional impairments (FIs) across familial, social, emotional, and academic/ occupational domains are frequently the reason for seeking treatment for ADHD.…”

Solriamfetol for attention deficit hyperactivity disorder

“…Mechanism is akin to bupropion which has similarly been used for ADHD. 2 It has favorable kinetics with renal clearance. Notable side effects, similar to stimulants, include headache, anxiety, appetite suppression and insomnia.…”

“…It is a wakefulness-promoting agent lasting 9 hours with an abuse potential. Mechanism is akin to bupropion which has similarly been used for ADHD 2 . It has favorable kinetics with renal clearance.…”

Personalizing Atomoxetine Dosing in Children with ADHD: What Can We Learn from Current Supporting Evidence

“…Available recommended medications for younger children and adolescents include stimulants (methylphenidate and amphetamines) and non-stimulants (atomoxetine, guanfacine and clonidine) (Elsayed, Yamamoto & Froehlich, 2020;Mechler, Banaschewski, Hohmann & Häge, 2021;Pozzi et al, 2018). However, approximately 25% of children with ADHD are stimulant "non-responders" and The improvement of ADHD symptoms is generally noted after 4 weeks of initiation of atomoxetine therapy (Cutler, Mattingly, Jain & O'Neal, 2022;Schwartz & Correll, 2014). However, the efficacy is not consistent among all patients (Newcorn, Sutton, Weiss & Sumner, 2009;Schwartz & Correll, 2014).…”