From the Guidelines
Atomoxetine works primarily as a selective norepinephrine reuptake inhibitor (SNRI) in the central nervous system, increasing synaptic noradrenaline by binding to the norepinephrine transporter and also increasing dopamine in the prefrontal cortex. The mechanism of action of atomoxetine is distinct from stimulant medications used for ADHD, which increase both dopamine and norepinephrine.
- Atomoxetine selectively inhibits the presynaptic norepinephrine transporter, preventing the reuptake of norepinephrine into the presynaptic neuron and thereby increasing extracellular norepinephrine concentrations, particularly in the prefrontal cortex 1.
- This increase in norepinephrine and dopamine in the prefrontal cortex contributes to its therapeutic effects without causing the same risk of abuse or dependence as stimulants.
- Atomoxetine is typically dosed at 40-100 mg daily, with a maximum of 100 mg/day for adults and 1.4 mg/kg/day for children, and reaches full effectiveness after 4-6 weeks of consistent use 1. The gradual onset of atomoxetine reflects its mechanism of slowly modulating neurotransmitter systems rather than directly stimulating them, which is in contrast to stimulants that work immediately.
- The most common adverse effects of atomoxetine include nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence 1.
- It is essential to monitor patients closely for suicidality, clinical worsening, and unusual changes of behavior, especially during the first few months of treatment or at times of dose change 1.
From the FDA Drug Label
The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies. The mechanism of action of atomoxetine is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter.
- The precise mechanism is unknown
- It is a selective norepinephrine reuptake inhibitor 2
From the Research
Mechanism of Action
- Atomoxetine is a selective norepinephrine reuptake inhibitor that acts almost exclusively on the noradrenergic pathway 3.
- Its mechanism of action in the control and maintenance of ADHD symptoms is thought to be through the highly specific presynaptic inhibition of norepinephrine 3.
- Atomoxetine inhibits the presynaptic norepinephrine transporter (NET), preventing the reuptake of NE throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex (PFC) 4.
Key Findings
- Atomoxetine has been shown to be effective in reducing symptoms of ADHD in children and adults, with improvements in ADHD symptoms, as assessed by investigator- and patient-rated scores, being greater with oral atomoxetine than with placebo 5, 6.
- Atomoxetine is generally well tolerated, with common adverse events including dry mouth, insomnia, nausea, decreased appetite, constipation, and dizziness 5, 3.
- Atomoxetine has a negligible risk of abuse or misuse and is not a controlled substance in the US 5, 6, 4.
Pharmacology
- Atomoxetine is mainly metabolized by the highly polymorphic drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6) 4.
- The clinical dose selection of atomoxetine is recommended based on both CYP2D6 genotype and the peak concentration 4.
- Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses 5, 4.