Atomoxetine, sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (SNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndrome (CDS). It may be used alone or along with psychostimulant medication. It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time, and emotional self-regulation. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.
Common side effects of atomoxetine include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness. Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. There is a lack of data regarding its safety during pregnancy; as of 2019, its safety during pregnancy and for use during breastfeeding is not certain.
It was approved for medical use in the United States in 2002. In 2023, it was the 161st most commonly prescribed medication in the United States, with more than 3million prescriptions.
Medical uses Attention deficit hyperactivity disorder Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD). It is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. One of the primary differences with the standard stimulant treatments for ADHD is that it has no known misuse potential. Meta-analyses and systematic reviews have found that atomoxetine has comparable efficacy and equal tolerability to methylphenidate in children and adolescents. In adults, efficacy and tolerability are equivalent. The benefits of atomoxetine against ADHD symptoms are dose-dependent until a plateau is reached.
While its efficacy may be less than that of lisdexamfetamine, there is some evidence supporting its use in combination with stimulants. Doctors may prescribe non-stimulants including atomoxetine when a person has bothersome side effects from stimulants; when a stimulant was not effective; in combination with a stimulant to increase effectiveness; when the cost of stimulants is prohibitive; or when there is concern about the misuse potential of stimulants in a patient with a history of substance use disorder.
Atomoxetine, similarly to stimulants, appears to reduce emotional lability associated with ADHD in adults.
Atomoxetine is thought to alleviate ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine levels in the prefrontal cortex, sharing 70–80% of the brain regions with stimulants in its produced effects.
The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent. A further 2 to 4 weeks may be required for the full therapeutic effects to be seen. Incrementally increasing response may occur up to 1 year or longer. The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg.
Other uses Cognitive disengagement syndrome Atomoxetine may be used to treat cognitive disengagement syndrome (CDS), as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment. In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate.
Nocturnal enuresis Atomoxetine has been studied in the treatment of nocturnal enuresis in children and is effective for this indication.
Excessive sleepiness Atomoxetine has wakefulness-promoting effects and is used off-label in the treatment of excessive sleepiness in for instance narcolepsy.
Traumatic brain injury Atomoxetine is sometimes used in the treatment of cognitive impairment and frontal lobe symptoms due to conditions like traumatic brain injury (TBI). It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition, lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome. A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects. Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid hemorrhage in a case report.
Available forms Atomoxetine is available in the form of oral capsules (10, 18, 25, 40, 60, 80, or 100mg) and in an oral solution (4mg/mL). It is taken once or twice daily.
Contraindications Contraindications of atomoxetine include:
Any cardiovascular disease including: Moderate to severe hypertension Atrial fibrillation Atrial flutter Ventricular tachycardia Ventricular fibrillation Ventricular flutter Advanced arteriosclerosis Severe cardiovascular disorders Uncontrolled hyperthyroidism Pheochromocytoma or history thereof Concomitant treatment with monoamine oxidase inhibitors (MAOIs) (and with at least 2weeks washout) Narrow-angle glaucoma Pregnancy and lactation Hypersensitivity to atomoxetine or other constituents
However, the FDA label states that in the case of cardiovascular disease, atomoxetine is only contraindicated in the case of severe cardiovascular disease. However, it states that atomoxetine should be used with caution in people with cardiovascular disease. In addition, consideration should be given to not using atomoxetine in people with clinically significant or serious structural cardiac abnormalities, as this may put them at greater risk of cardiovascular complications with atomoxetine.
A precaution or relative contraindication is concomitant use of strong CYP2D6 inhibitors, which may necessitate atomoxetine dose adjustment.
Side effects Common side effects include abdominal pain, decreased appetite, nausea, erectile dysfunction, feeling tired, dizziness, and urinary retention. Atomoxetine has been found to modestly increase heart rate and blood pressure. A 2020 meta-analysis found that atomoxetine was associated with appetite suppression, weight loss, and hypertension, rating it as a "potentially least preferred agent based on safety" for treating ADHD. The drug can produce insomnia as a side effect, especially in CYP2D6 poor metabolizers, but has less overall risk of insomnia than methylphenidate or amphetamines.
As of 2019, safety in pregnancy and breastfeeding is not clear; a 2018 review stated that, "because of lack of data, the treating physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy."
Serious side effects may include angioedema, liver problems, psychosis, heart problems, suicide, and aggression. Atomoxetine does not appear to increase the risk of stroke in adults nor the risk of sudden death. On the other hand, the FDA label notes that sudden death, stroke, and heart attack have been reported in association with atomoxetine and that such complications may be more likely in people with pre-existing cardiovascular disease. The drug can dramatically increase blood pressure in people with central autonomic failure, even at very low doses. Rarely, atomoxetine can cause drug-induced liver injury or liver failure.
Atomoxetine may increase the likelihood of aggression and hostility in children with ADHD, although such events are rare. The U.S. Food and Drug Administration (FDA) has issued a black box warning for suicidal behavior/ideation. Similar warnings have been issued in Australia. Unlike stimulant medications, atomoxetine does not have misuse liability or the potential to cause withdrawal effects upon abrupt discontinuation.
Atomoxetine has been found to directly inhibit hERG potassium currents with an of 6,300nM, which has the potential to cause arrhythmia. No substantial QTc interval changes were observed in a clinical study of atomoxetine in CYP2D6 poor metabolizers. However, small changes could not be ruled out, and there was a slight but significant increase in QTc interval with higher atomoxetine concentrations. QT prolongation has been reported with atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used with other medications that may prolong the QT interval, concomitantly with CYP2D6 inhibitors, and caution to be used in poor metabolizers.
Unlike α2-adrenergic receptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant withdrawal symptoms being observed.
Overdose Atomoxetine can lead to cardiac complications, with severe overdose requiring intensive medical care to avoid death.
Interactions Atomoxetine is a substrate for CYP2D6. Concurrent treatment with strong CYP2D6 inhibitors such as bupropion, fluoxetine, paroxetine, and quinidine has been shown to substantially increase atomoxetine exposure, as well as increase N-desmethylatomoxetine levels and decrease 4-hydroxyatomoxetine levels. Bupropion increased atomoxetine exposure by 5.1-fold and decreased 4-hydroxyatomoxetine-O-glucuronide exposure by 1.5-fold. Similarly, paroxetine increased atomoxetine steady-state peak levels by 3.5-fold, total exposure (over 12hours) by 6.5-fold, and elimination half-life by 2.5-fold. Findings were analogous for fluoxetine and quinidine. CYP2D6 inhibitors do not appear to affect atomoxetine metabolism in CYP2D6 poor metabolizers. Dosage adjustment of atomoxetine may be necessary in people taking strong CYP2D6 inhibitors.
Atomoxetine does not show clinically important inhibition or induction of cytochrome P450 (CYP450) enzymes including CYP1A2, CYP3A, CYP2D6, and CYP2C9. It did not affect the pharmacokinetics of the CYP2D6 substrate desipramine, whereas it increased exposure to the CYP3A4 substrate midazolam by only 15%. Atomoxetine is a moderate to potent inhibitor of P-glycoprotein.
Other notable drug interactions include:
Antihypertensive agents, due to atomoxetine acting as an indirect sympathomimetic Indirect-acting sympathomimetics, such as pseudoephedrine, other norepinephrine reuptake inhibitors (NRIs), or MAOIs Direct-acting sympathomimetics, such as phenylephrine or other α1-adrenergic receptor agonists, including vasopressors such as dobutamine or isoprenaline and β2-adrenergic receptor agonists Highly plasma protein-bound drugs: atomoxetine has the potential to displace these drugs from plasma proteins which may potentiate their adverse or toxic effects. In vitro, atomoxetine does not affect the plasma protein binding of aspirin, desipramine, diazepam, paroxetine, phenytoin, or warfarin
Drugs affecting gastric pH have no effect on the bioavailability or pharmacokinetics of atomoxetine.
Atomoxetine prevents norepinephrine release induced by amphetamines and has been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.
Pharmacology Pharmacodynamics + Atomoxetine (and metabolites) activities Site 77 43 5 3 92 DAT 1,451 >1,000 422 (antagonist?) 300 (antagonist?) >1,000? 95 (partial agonist) σ1 >1,000 GABAA 200 >30,000 >10,000 NMDA 0.66–3,470a 5-HT1A >1,000 5-HT1B >1,000 5-HT1D >1,000 5-HT2 2,000 1,000 1,700 5-HT6 >1,000 5-HT7 >1,000 α1 11,400 20,000 19,600 α2A 29,800 >30,000 >10,000 β1 18,000 56,100 32,100 M1 >100,000 >100,000 >100,000 M2 >100,000 >100,000 >100,000 D1 >10,000 >10,000 >10,000 D2 >10,000 >10,000 >10,000 H1 12,100 >100,000 >100,000 Kir3.1/3.2 10,900b Kir3.2 12,400b Kir3.1/3.4 6,500b hERG 6,300 20,000 5,710 Notes: Values are Ki (nM). The smaller the value, the more avidly the drug binds to the site. All values are for human receptors unless otherwise specified. Footnotes: a = Rat cortex. b = Xenopus oocytes. Additional sources: