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Atomoxetine
Atomoxetine is a selective norepinephrine reuptake inhibitor indicated for ADHD treatment1. It is tentatively categorized as a stimulant, although it is generally described as a non-stimulant medication with atypical pharmacology. Common adverse effects include abdominal pain, reduced appetite, nausea, fatigue, and dizziness1; reported serious risks include liver problems1, psychosis1, cardiovascular events1, aggression1, and suicidality1. It is taken orally1.
Dosage & Duration
Dosage
Doses are population estimates that vary widely between individuals.
Duration
Subjective Effects
Pharmacology
Pharmacodynamics
Atomoxetine inhibits the presynaptic norepinephrine transporter, reducing norepinephrine reuptake throughout the brain and increasing norepinephrine and dopamine concentrations in the prefrontal cortex, where dopamine transporter expression is minimal. In rats and mice, these catecholamine changes were region-specific, and rat studies found no corresponding dopamine increase in the striatum or nucleus accumbens. Rhesus monkey PET imaging measured greater than 90% NET occupancy and greater than 85% SERT occupancy, but SERT inhibition at clinical doses in humans remains uncertain because rodent microdialysis and a human platelet serotonin uptake study did not show functional evidence of serotonin reuptake inhibition. At therapeutic concentrations, atomoxetine produced use-dependent open-channel block of NMDA receptors in rat cortical neurons and reversibly inhibited GIRK currents in Xenopus oocytes, although the contribution of GIRK inhibition to its therapeutic effects is unknown. Atomoxetine also directly inhibited hERG potassium currents with an IC50 of 6.3 μM.
Pharmacokinetics
Atomoxetine is rapidly and completely absorbed after oral administration, but CYP2D6-dependent first-pass hepatic metabolism produces an absolute bioavailability of 63% in extensive metabolizers and 94% in poor metabolizers. CYP2D6 is the primary metabolic pathway, with a major oxidative metabolite undergoing rapid glucuronidation; when CYP2D6 activity is absent, this metabolite forms more slowly through other cytochrome P450 enzymes, while CYP2C19 and other enzymes produce a less active minor metabolite. CYP2D6 poor metabolizers have approximately 10-fold higher steady-state exposure, 5-fold higher peak plasma concentrations, and slower elimination, with a plasma half-life of 21.6 hours, while the generally reported half-life is 3 to 5.6 hours. Atomoxetine is 98.7% plasma protein bound and is extensively transformed before excretion, with more than 80% of the dose eliminated in urine, less than 17% in feces, and less than 3% excreted unchanged.
Interactions
An unlisted combination is an unknown one, not a safe one. Check a dedicated combination chart before mixing.
Tolerance
Harm Potential
Toxicity
Severe overdose can cause cardiac complications and may require intensive medical care to avoid death2; no human lethal dose estimate is established here.
Sudden death, stroke, and myocardial infarction have been reported in adults taking atomoxetine at usual doses for ADHD1. QT prolongation has been reported at therapeutic doses and in overdose, and severe overdose can cause cardiac complications.
Rare clinically significant liver injury, including rare liver failure, has been reported in postmarketing use and was considered probably or possibly related to atomoxetine1.
Psychosis Risk
Treatment-emergent psychotic or manic symptoms, including hallucinations and delusional thinking, can occur at usual doses in children and adolescents without a prior history of psychotic illness or mania1.
Seizure Risk
Seizures have been reported in some atomoxetine overdoses1.
History & Culture
Development and approval
Atomoxetine was initially developed as an antidepressant, but it was found to be insufficiently effective for depression. Its effectiveness for attention deficit hyperactivity disorder led to U.S. Food and Drug Administration approval for ADHD treatment in 2002.4 The drug
Legality
By Country
United StatesPrescription only
CanadaPrescription onlyReferences
Citations
Article Status
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