Atomoxetine

Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor used for the treatment of attention deficit hyperactivity disorder (ADHD). Also known as the marketed product Strattera, atomoxetine is used with other treatment modalities (psychological, educational, cognitive behaviour therapy, etc) to improve developmentally inappropriate symptoms associated with ADHD including distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. Although the underlying pathophysiology that causes ADHD remains unclear, evidence suggests that dysregulation in noradrenergic and dopaminergic pathways plays a critical role in suboptimal executive functioning within prefrontal regions of the brain, which are involved in attention and memory.^A178090 Atomoxetine has been shown to specifically increase NA and DA within the prefrontal cortex, but not in the nucleus accumbens (NA) or striatum.^A18262 This is beneficial in the treatment of ADHD as DA activation in the subcortical NA and striatum is associated with many stimulant-associated side effects and an increase in abuse potential, which is a limiting factor associated with the use of stimulant medications such as DB00422, DB01576, and DB01255.^A18262 Use of non-stimulant medications such as atomoxetine is therefore thought to offer a clinical advantage over the use of traditional medications for the management of ADHD. More recently, positron emission tomography (PET) imaging studies in rhesus monkeys have shown that atomoxetine also binds to the serotonin transporter (SERT),^A178111 and blocks the N-methyl-d-aspartate (NMDA) receptor,^A18263 indicating a role for the glutamatergic system in the pathophysiology of ADHD.

Long-acting formulations of psychostimulants (such as DB00422, DB01576, and DB01255) are typically considered the most effective and first-line treatment for ADHD in adults and children as recommended by CADDRA (Canadian ADHD Resource Alliance).^L6037 However, these stimulant medications are limited by dose-related side effects and concerns of abuse. Many contain a blackbox warning stating that CNS stimulants, including methylphenidate-containing products and amphetamines, have a high potential for abuse and dependence. In particular, increased dopamine in key areas caused by these stimulant medications is associated with their reinforcing and addictive properties, and even amplifies the potency and reinforcing effects of other drugs of abuse such as amphetamines, making ADHD sufferers more susceptible to their addictive effects.^A177556 Concerns about abuse potential have spurred research into medications with fewer effects on DA and the use of non-stimulant ADHD medications including atomoxetine, DB00745 and DB01018. The non-stimulant norepinephrine/dopamine reuptake inhibitor DB01156 (commonly used for the treatment of depression and for smoking cessation) has also been shown to be effective in the treatment of ADHD.^A178099