It was approved for medical use in the United States in 2002.[12] In 2023, it was the 161st most commonly prescribed medication in the United States, with more than 3million prescriptions.[28][29]
Atomoxetine is approved for use in children, adolescents, and adults.[4] However, its efficacy has not been studied in children under six years old.[7] One of the primary differences with the standardstimulant treatments for ADHD is that it has little known abuse potential.[7]Meta-analyses andsystematic reviews have found that atomoxetine has comparable efficacy and equal tolerability tomethylphenidate in children and adolescents. In adults, efficacy and tolerability are equivalent.[21][22][23][24]
While its efficacy may be less than that oflisdexamfetamine,[30] there is some evidence that it may be used in combination with stimulants.[16] 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;[31][32] when the cost of stimulants is prohibitive; or when there is concern about the abuse potential of stimulants in a patient with a history ofsubstance use disorder.
Atomoxetine alleviates ADHD symptoms throughnorepinephrine reuptake inhibition and by indirectly increasing dopamine in theprefrontal cortex,[33] sharing 70-80% of the brain regions with stimulants in their produced effects.[34]
The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent.[6][35][36] A further 2 to 4 weeks may be required for the full therapeutic effects to be seen.[37][35] Incrementally increasing response may occur up to 1 year or longer.[36][38] The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg.[4]
Atomoxetine is asubstrate forCYP2D6. Concurrent treatment with a CYP2D6 inhibitor such asbupropion,fluoxetine, orparoxetine has been shown to increase plasma atomoxetine by 100% or more, as well as increaseN-desmethylatomoxetine levels and decrease plasma 4-hydroxyatomoxetine levels by a similar degree.[54][55][56]
Atomoxetine has been found to directly inhibithERG potassium currents with anIC50 of 6.3 μM, which has the potential to causearrhythmia.[55][57]QT prolongation has been reported with atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used with othermedications that may prolong the QT interval, concomitantly with CYP2D6 inhibitors, and caution to be used in poor metabolizers.[55]
Other notable drug interactions include:
Antihypertensive agents, due to atomoxetine acting as an indirect sympathomimetic
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 ofaspirin,desipramine,diazepam,paroxetine,phenytoin, orwarfarin[9][58]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All values are for human receptors unless otherwise specified.arat cortex.bXenopus oocytes. Additional sources:[65][64][9][58]
Atomoxetine inhibits the presynapticnorepinephrine transporter (NET), preventing the reuptake of norepinephrine throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex, wheredopamine transporter (DAT) expression is minimal.[9] In rats, atomoxetine increasedprefrontal cortexcatecholamine concentrations without alteringdopamine levels in thestriatum ornucleus accumbens; in contrast,methylphenidate, adopamine reuptake inhibitor, was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree.[66][65] In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.[67]
Atomoxetine's status as aserotonin transporter (SERT) inhibitor at clinical doses in humans is uncertain. APET imaging study onrhesus monkeys found that atomoxetine occupied >90% and >85% of neural NET and SERT, respectively.[68] However, both mouse and ratmicrodialysis studies have failed to find an increase in extracellularserotonin in the prefrontal cortex following acute or chronic atomoxetine treatment.[65][67] Supporting atomoxetine's selectivity, a human study found no effects on platelet serotonin uptake (a marker of SERT inhibition) and inhibition of thepressor effects oftyramine (a marker of NET inhibition).[69]
Atomoxetine has been found to act as anNMDA receptor antagonist in rat cortical neurons at therapeutic concentrations.[70][71] It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site.[70][71] Atomoxetine's ability to increase prefrontal cortex firing rate in anesthetized rats could not be blocked byD1 orα1-adrenergic receptor antagonists, but could be potentiated byNMDA or anα2-adrenergic receptor antagonist, suggesting a glutaminergic mechanism.[72] InSprague Dawley rats, atomoxetine reducesNR2B protein content without altering transcript levels.[73] Aberrant glutamate and NMDA receptor function have been implicated in the etiology ofADHD.[74][75]
Atomoxetine also reversibly inhibitsGIRK currents inXenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner.[76] Kir3.1/3.2ion channels are opened downstream ofM2,α2,D2, andA1 stimulation, as well as otherGi-coupled receptors.[76] Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers.[76] It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.
4-Hydroxyatomoxetine, the major active metabolite of atomoxetine in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity foropioid receptors, acting as an antagonist atμ-opioid receptors and a partial agonist atκ-opioid receptors.[64] It is not known whether this action at the kappa-opioid receptor leads to CNS-related adverse effects.
Orally administered atomoxetine is rapidly and completely absorbed.[9] First-pass metabolism by the liver is dependent onCYP2D6 activity, resulting in anabsolute bioavailability of 63% for extensive metabolizers and 94% for poor metabolizers.[9] Maximum plasma concentration is reached in 1–2 hours.[9] If taken with food, the maximum plasma concentration decreases by 10–40% and delays thetmax by 3 hours.[9] Drugs affecting gastric pH have no effect on oral bioavailability.[4]
Followingintravenous delivery, atomoxetine has avolume of distribution of 0.85 L/kg (indicating distribution primarily in total body water), with limited partitioning into red blood cells.[9][77] It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%).[9][58] Its metaboliteN-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.[9]
The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours.[9][10] As atomoxetine is metabolized by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolizers.[10] Among CYP2D6 extensive metabolizers, the half-life of atomoxetine averaged 5.34 hours and the half-life of the active metaboliteN-desmethylatomoxetine was 8.9 hours.[9][78] By contrast, among CYP2D6 poor metabolizers the half-life of atomoxetine averaged 20.0 hours and the half-life ofN-desmethylatomoxetine averaged 33.3 hours.[9][78]Steady-state levels of atomoxetine are typically achieved at or around day 10 of regular dosing, withtrough plasma concentrations (Ctrough) residing around 30–40°ng/mL; however, both the time to steady-state levels and Ctrough are expected to vary based on a patient'sCYP2D6 profile.[79][80]
Atomoxetine,N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhibition ofCYP1A2 andCYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6 and 17 μmol/L.[citation needed] Plasma concentrations of 4-hydroxyatomoxetine andN-desmethylatomoxetine at steady state are 1% and 5% that of atomoxetine in CYP2D6 extensive metabolizers, and 0.1% and 45% that of atomoxetine in CYP2D6 poor metabolizers, respectively.[4]
Atomoxetine is excreted unchanged in urine at <3% in both extensive and poor CYP2D6 metabolizers, with >96% and 80% of a total dose being excreted in urine, respectively.[9] The fractions excreted in urine as 4-hydroxyatomoxetine and its glucuronide account for 86% of a given dose in extensive metabolizers, but only 40% in poor metabolizers.[9] CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namelyN-desmethylatomoxetine and 2-hydroxymethylatomoxetine and theirconjugates.[9]
Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higherarea-under-the-curve (AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolizers.[9]
Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolizers.[9]
Atomoxetine may be quantitated in plasma, serum, or whole blood to distinguish extensive versus poor metabolizers in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage.[83]
Atomoxetine is manufactured, marketed, and sold in the United States as thehydrochloride salt (atomoxetine HCl) under the brand name Strattera byEli Lilly and Company, the originalpatent-filing company and current U.S. patent owner. Atomoxetine was initially intended to bedeveloped as an antidepressant, but it was found to be insufficiently efficacious for treating depression. It was, however, found to be effective for ADHD and was approved by the FDA in 2002, for the treatment of ADHD. Its patent expired in May 2017.[84] On 12 August 2010, Lilly lost a lawsuit that challenged its patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market.[85] On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.[86] In a 29 July 2011 conference call, however, Sun Pharmaceutical's Chairman stated "Lilly won that litigation on appeal so I think [generic Strattera]'s deferred."[87]
In 2017 the FDA approved the generic production of atomoxetine by four pharmaceutical companies.[88]
In India, atomoxetine is sold under brand names including Axetra, Axepta, Attera, Tomoxetin, and Attentin. In Australia, Canada, Italy, Portugal, Romania, Spain, Switzerland, and the US, atomoxetine is sold under the brand name Strattera. In France, hospitals dispense atomoxetine under the brand name Strattera (it is not marketed in France). In the Czech Republic, it is sold under brand names including Mylan. In Poland, it is sold under the brand name Auroxetyn. In Indonesia, it is sold under the brand name Xenocy. In Iran, atomoxetine is sold under brand names including Stramox. In Brazil, it is sold under the brand name Atentah. In Turkey, it is sold under the brand names Attex, Setinox, and Atominex. In 2017, ageneric version was approved in the United States.[88]
There has been some suggestion that atomoxetine might be a helpful adjunct in people withmajor depression, particularly in cases with concomitant ADHD.[90]
Atomoxetine may be used in those with ADHD andbipolar disorder although such use has not been well established.[91] Some benefit has also been seen in people with ADHD andautism.[92] As with other norepinephrine reuptake inhibitors it appears to reduce anxiety and depression symptoms, although research has focused mainly on specific patient groups such as those with concurrent ADHD[93] or methamphetamine dependence.[94]
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^Barkley RA (2015)."Concentration deficit disorder (sluggish cognitive tempo)."(PDF).Attention-deficit hyperactivity disorder: A handbook for diagnosis and treatment. The Guilford Press. pp. 81–115.Archived(PDF) from the original on 16 January 2024. Retrieved28 February 2024.
^Termine C, Selvini C, Rossi G, Balottin U (2013). "Emerging treatment strategies in Tourette syndrome: what's in the pipeline?".International Review of Neurobiology.112:445–80.doi:10.1016/B978-0-12-411546-0.00015-9.PMID24295630.Atomoxetine is a nonstimulant drug used to treat ADHD (Perwien et al., 2006) that acts as a presynaptic blocker of noradrenalin reuptake (Swanson et al., 2006).
^Whiskey E, Taylor D (August 2013). "A review of the adverse effects and safety of noradrenergic antidepressants".Journal of Psychopharmacology.27 (8):732–739.doi:10.1177/0269881113492027.PMID23784737.In adult ADHD controlled trials, the rates of urinary retention (1.7%, 9/540) and urinary hesitation (5.6%, 30/540) were increased among atomoxetine subjects compared with placebo subjects (0%, 0/402; 0.5%, 2/402, respectively).
^Wernicke JF, Adler L, Spencer T, West SA, Allen AJ, Heiligenstein J, et al. (February 2004). "Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: a prospective, placebo-controlled assessment".Journal of Clinical Psychopharmacology.24 (1):30–35.doi:10.1097/01.jcp.0000104907.75206.c2.PMID14709944.S2CID37636280.
^Heal DJ, Smith SL, Findling RL (2012). "ADHD: current and future therapeutics".Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment. Current Topics in Behavioral Neurosciences. Vol. 9. pp. 361–390.doi:10.1007/7854_2011_125.ISBN978-3-642-24611-1.PMID21487953.Adjunctive therapy with DL-methylphenidate in atomoxetine partial responders has been successful (Wilens et al. 2009), but this also increases the rates of insomnia, irritability and loss of appetite (Hammerness et al. 2009). This combination therapy has not included amphetamine because blockade of NET by atomoxetine prevents entry of amphetamine into presynaptic noradrenergic terminals (Sofuoglu et al. 2009).
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^A US patent 4018895 A, Bryan B. Molloy & Klaus K. Schmiegel, "Aryloxyphenylpropylamines in treating depression", published 19 April 1977, assigned to Eli Lilly And Company
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^Siegel M, Erickson C, Frazier JA, Ferguson T, Goepfert E, Joshi G, et al. (Autism Society of America) (2016).Autism Spectrum Disorder Parents Medication Guide(PDF). Washington, DC: American Academy of Child and Adolescent Psychiatry. p. 13.Archived(PDF) from the original on 11 April 2017.Atomoxetine (Strattera) has also been researched in controlled studies for treatment of ADHD in children with autism, and showed some improvements, particularly for hyperactivity and impulsivity
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