Atomoxetine: Classification, Mechanism of Action, and Side Effects
Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor (SNRI) that increases both noradrenaline and dopamine levels in the prefrontal cortex by binding to the norepinephrine transporter, with a distinct side effect profile including nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence. 1
Classification and Pharmacology
- Atomoxetine is classified as a selective norepinephrine reuptake inhibitor (SNRI), not a stimulant, making it the first non-stimulant medication approved for ADHD treatment 1
- Unlike stimulants, atomoxetine is not a controlled substance in the US, as it has negligible risk of abuse or misuse 2, 3
- Atomoxetine is FDA-approved for ADHD treatment in both children/adolescents and adults 1, 4
- It is available in capsules containing 10,18,25,40,60,80, or 100 mg of atomoxetine hydrochloride and as an oral solution (4 mg/ml) 1
Mechanism of Action
- Atomoxetine selectively inhibits presynaptic norepinephrine transporters, increasing synaptic noradrenaline levels 1
- In the prefrontal cortex, norepinephrine transporters also regulate dopamine reuptake (as dopamine transporters are scarce in this region) 1
- This dual action increases both noradrenaline and dopamine concentrations in the prefrontal cortex synapses 1
- The medication has high affinity and selectivity for norepinephrine transporters but little or no affinity for other neurotransmitter receptors 2
Pharmacokinetics
- Atomoxetine is orally administered and can be given either as a single daily dose or split into two evenly divided doses 1, 2
- It is primarily metabolized through the cytochrome P450 2D6 (CYP2D6) pathway 1
- Approximately 7% of the population are poor CYP2D6 metabolizers, resulting in higher plasma levels and longer half-lives, potentially increasing adverse effects 1, 5
- Some selective serotonin reuptake inhibitors (SSRIs) can elevate serum atomoxetine levels through CYP2D6 inhibition 1
- Titration follows a sequential, weight-based approach with maximum recommended dosage of 1.4 mg/kg/day or 100 mg/day, whichever is lower 1
Common Side Effects
The most common adverse effects in children and adolescents include: 1, 5
- Gastrointestinal effects: nausea, vomiting, abdominal pain
- Decreased appetite
- Fatigue and somnolence
- Weight decreased
In adults, common side effects include: 5, 4
- Dry mouth
- Insomnia
- Nausea
- Decreased appetite
- Constipation
- Dizziness
- Sexual dysfunction (in approximately 2% of adult patients) 6
Important Safety Concerns and Monitoring
Suicidal ideation: Analysis of twelve placebo-controlled trials showed increased risk of suicidal ideation in children and adolescents (but not in adults) 1
Cardiovascular effects: Atomoxetine can cause statistically but not clinically significant increases in heart rate and blood pressure 2
Growth effects: Initial loss in expected height and weight may occur but typically returns to normal in the longer term 2
Special warnings exist for: 1
- Preexisting cardiovascular diseases/significant cardiac abnormalities
- Emergent psychotic or manic symptoms
- Bipolar disorder
- Aggressive behavior or hostility
- Possible allergic reactions
- Effects on urine outflow
- Priapism (rare)
Liver injury: Rare cases of serious liver injury have been reported 2
Clinical Considerations
Atomoxetine has a slower onset of action (6-12 weeks) compared to stimulants 1
It provides "around-the-clock" symptom control unlike stimulants 1
Atomoxetine may be particularly useful for: 3, 4
- Patients at risk of substance abuse
- Those with comorbid anxiety or tics
- Patients who do not wish to take a controlled substance
Poor CYP2D6 metabolizers experience more adverse effects than extensive metabolizers 5
Children treated with atomoxetine should be monitored closely for suicidality, clinical worsening, and unusual behavior changes, especially during the first few months of treatment or at times of dose change 1