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What value do norepinephrine/dopamine dual reuptake inhibitors have to the current treatment of adult attention deficit hyperactivity disorder (ADHD) treatment armamentarium?

Attention deficit/hyperactivity disorder (ADHD) is defined as a persistent pattern of inattention and/or hyperactivity/impulsivity that interferes with functioning or development. ADHD is the most common neurodevelopmental disorder diagnosed in childhood and persists into adolescence and adulthood in 40%-70% of cases [1]. In adults, hyperactivity usually improves, while executive dysfunctions (such as inattention, disorganization, and impaired working memory), behavioral and emotional impulsivity, and emotional dysregulation (ED) persist or even worsen, resulting in reduced quality of life and impaired interpersonal, occupational, and social functioning. Additionally, most adults with ADHD have numerous psychiatric comorbidities and complications, such as alcohol/substance use, mood, anxiety, eating, impulse control, and personality disorders [2], which are often the reason why patients seek psychiatric care. In many cases, ADHD symptoms are not even recognized because psychiatric comorbidities complicate the clinical picture, making the diagnostic process more difficult. Finally, in a substantial proportion of cases, psychiatric comorbidity (e.g. a severe psychotic mood episode, severe addictive disorders, etc.) constitutes a therapeutic priority. However, the coexisting symptoms of ADHD can strongly influence the clinical picture and drug response and should always be considered during treatment management. Although multiple neurotransmitters seem to be involved in the development of ADHD (serotonin, acetylcholine, glutamate, opioids), dopaminergic and noradrenergic pathways are the most investigated. In individuals with ADHD, a general reduction in brain size is observed, particularly in the prefrontal cortex, corpus callosum, cerebellar vermis, caudate nucleus, and globus pallidus, and several symptoms can be traced to deficient dopaminergic and noradrenergic transmission in different brain circuits [3]. In addition, polymorphisms in genes encoding for dopamine D4 and D5 receptors and the dopamine transporter (DAT), causing deficits in dopaminergic transmission, have been associated with ADHD [4], although subsequent large GWAS studies have not confirmed this finding [5]. In youths and adults with ADHD, currently approved pharmacological agents act by increasing catecholaminergic transmission and include stimulant and non-stimulant medications [6]. Psychostimulant agents (i.e. methylphenidate and amphetamines) are the mainstay of ADHD treatment both in pediatric and adult populations, and act as norepinephrine/ dopamine dual reuptake inhibitors. On the other hand, most non-stimulant compounds (i.e. atomoxetine, viloxazine) target mostly the noradrenergic system. Nonetheless, atomoxetine also seems to indirectly increase dopaminergic tone in the prefrontal cortex in animal models [7], while viloxazine, which has recently been approved for the treatment of ADHD in children and adolescents, acts as a serotonin and norepinephrine modulating medication [8]. Third-line drugs include alpha 2A-adrenergic receptor agonists (guanfacine, clonidine), bupropion, modafinil, and tricyclic antidepressant (e.g. desipramine, nortriptyline).