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.
Highlights
As the most common neurodevelopmental disorder of childhood, attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity, and impulsivity
Atomoxetine was the first nonstimulant medication approved by the Food and Drug Administration (FDA) for the treatment of ADHD based on a series of doubleblind, randomized controlled trials (RCTs) in children ≥6 years of age, adolescents, and adults
Results of the dasotraline-ADHD clinical development program were reviewed by the FDA, which rejected approval pending additional efficacy and tolerability data.[27]
Summary
As the most common neurodevelopmental disorder of childhood, attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity, and impulsivity. Recent findings regarding antidepressant resistance suggest that this approach may need to be reconsidered.[4] The risk of antidepressant resistance was found to be >2-fold higher in patients with major depression and comorbid ADHD vs major depression alone.[4] Concomitant ADHD treatment was associated with a significantly lower risk of antidepressant resistance, leading to the conclusion that prompt and regular treatment of ADHD in dual-diagnosis patients may reduce the risk of antidepressant resistance.[4] Because the functional impairments of ADHD can exacerbate underlying mood disorders, anxiety disorders, and substance abuse, the careful treatment of ADHD may provide a more favorable environment for effective treatment of these psychiatric comorbidities.[1]
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