Atomoxetine

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Atomoxetine, formerly sold under the brand name Strattera,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD)<ref name=AHFS2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and, to a lesser extent, cognitive disengagement syndrome (CDS).<ref name="Atomoxetine-Related Change in Slugg">Template:Cite journal</ref><ref name="Report of a Work Group on Sluggish">Template:Cite journal</ref><ref name="Atomoxetine improved attention in c">Template:Cite journal</ref> It may be used alone or along with stimulant medication.<ref name="Tr2013">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time,<ref>Template:Cite journal</ref> and emotional self-regulation.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Use of atomoxetine is only recommended for those who are at least six years old.<ref name="AHFS2019" /> It is taken orally.<ref name="AHFS2019" /> The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.<ref name="Hanwella_2011" /><ref name="Rezaei_2016" /><ref name="Hazell_2011" /><ref name="Bushe_2016" />

Common side effects of atomoxetine include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness.<ref name=AHFS2019/> Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression.<ref name=AHFS2019/><ref name=BNF76>Template:Cite book</ref> 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.<ref name=Preg2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name= Ornoy2018/>

It was approved for medical use in the United States in 2002.<ref name=AHFS2019/> In 2022, it was the 213th most commonly prescribed medication in the United States, with more than 1Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD).<ref name="Strattera FDA label" />

Attention deficit hyperactivity disorder

Atomoxetine is approved for use in children, adolescents, and adults.<ref name="Strattera FDA label" /> However, its efficacy has not been studied in children under six years old.<ref name = TGA>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> One of the primary differences with the standard stimulant treatments for ADHD is that it has little known abuse potential.<ref name = TGA /> 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.<ref name="Hanwella_2011">Template:Cite journal</ref><ref name="Rezaei_2016">Template:Cite journal</ref><ref name="Hazell_2011">Template:Cite journal</ref><ref name="Bushe_2016">Template:Cite journal</ref>

While its efficacy may be less than that of lisdexamphetamine,<ref>Template:Cite journal</ref> there is some evidence that it may be used in combination with stimulants.<ref name=Tr2013/> 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;<ref name="Home combination">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="NIMH 2019">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> when the cost of stimulants is prohibitive; or when there is concern about the abuse potential of stimulants in a patient with a history of substance use disorder.

Atomoxetine alleviates ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine in the prefrontal cortex,<ref name="Koda_2010">Template:Cite journal</ref> sharing 70-80% of the brain regions with stimulants in their produced effects.<ref name="Schulz_2012">Template:Cite journal</ref>

Unlike α₂-adrenergic receptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant withdrawal symptoms being observed.<ref name = TGA />

The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent.<ref name = MSR /><ref name="pmid23438503">Template:Cite journal</ref><ref name="pmid26730199">Template:Cite journal</ref> A further 2 to 4 weeks may be required for the full therapeutic effects to be seen.<ref name="Maudsley">Template:Cite book</ref><ref name="pmid23438503" /> Incrementally increasing response may occur up to 1 year or longer.<ref name="pmid26730199" /><ref name="pmid26349559">Template:Cite journal</ref> The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg.<ref name="Strattera FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Other uses

Cognitive disengagement syndrome

Atomoxetine may be used to treat cognitive disengagement syndrome (CDS),<ref name="Report of a Work Group on Sluggish"/> as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment.<ref name="Report of a Work Group on Sluggish"/><ref name="Atomoxetine-Related Change in Slugg"/><ref name="Atomoxetine improved attention in c"/> In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite book</ref>

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).<ref name="pmid16456396">Template:Cite journal</ref><ref name="pmid32044373">Template:Cite journal</ref> It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition,<ref name="pmid24295630">Template:Cite journal</ref> lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome.<ref name="pmid16456396" /> A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects.<ref name="pmid26624881">Template:Cite journal</ref> Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid hemorrhage in a case report.<ref name="pmid32044373" /><ref name="pmid20661027">Template:Cite journal</ref>

Contraindications

Contraindications include:<ref name = TGA />

• 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
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs)
• Narrow-angle glaucoma

Adverse effects

Common side effects include abdominal pain, decreased appetite, nausea, erectile dysfunction, feeling tired, dizziness<ref name="AHFS2019" /> and urinary retention.<ref>Template:Cite journal</ref> Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression.<ref name="AHFS2019" /><ref name="BNF76" /> A 2020 meta-analysis found that atomoxetine was associated with anorexia, weight loss, and hypertension, rating it as a "potentially least preferred agent based on safety" for treating ADHD.<ref name= Solmi2020>Template:Cite journal</ref><ref>Template:Cite journal</ref> As of 2019, safety in pregnancy and breastfeeding is not clear;<ref name="Preg2019" /> a 2018 review stated that, "because of lack of data, the treating physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy."<ref name= Ornoy2018>Template:Cite journal</ref>

The U.S. Food and Drug Administration (FDA) has issued a black box warning for suicidal behavior/ideation.<ref name="DM" /> Similar warnings have been issued in Australia.<ref name="TGA" /><ref>Template:Cite journal</ref> Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects upon abrupt discontinuation.<ref name="TGA" /><ref>Template:Cite journal</ref>

Overdose

Atomoxetine can lead to cardiac complications, with severe overdose requiring intensive medical care to avoid death. <ref>Template:Cite journal</ref>

Interactions

Atomoxetine is a substrate for CYP2D6. Concurrent treatment with a CYP2D6 inhibitor such as bupropion, fluoxetine, or paroxetine has been shown to increase plasma atomoxetine by 100% or more, as well as increase N-desmethylatomoxetine levels and decrease plasma 4-hydroxyatomoxetine levels by a similar degree.<ref name = PMID27518170>Template:Cite journal</ref><ref name = PMID21765848>Template:Cite journal</ref><ref name = PMID12412820>Template:Cite journal</ref>

Atomoxetine has been found to directly inhibit hERG potassium currents with an IC₅₀ of 6.3 μM, which has the potential to cause arrhythmia.<ref name = PMID21765848/><ref name = PMID19154426>Template:Cite journal</ref> 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.<ref name = PMID21765848/>

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<ref name="Sa2005">Template:Cite journal</ref><ref name = part2>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

Atomoxetine prevents norepinephrine release induced by amphetamines and has been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.<ref name="TreuerGauMéndez2013">Template:Cite journal</ref><ref name="HealSmithFindling2012">Template:Cite book</ref><ref name="SofuogluPolingHill2009">Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

citation

CitationClass=web }}</ref><ref name="Upadhyaya Desaiah Schuh Bymaster pp. 189–200">Template:Cite journal</ref>
Site	Template:Abbr	Template:Abbr	Template:Abbr
Template:Abbrlink	77	43	Template:Abbr
Template:Abbrlink	5	3	92
DAT	1,451	Template:Abbr	Template:Abbr
Template:Abbrlink	>1,000<ref name="PMID15225731" />	422 (antagonist?)	Template:Abbr
Template:Abbrlink	Template:Abbr	300 (antagonist?)	Template:Abbr
Template:Abbrlink	>1,000?<ref name="PMID15225731" />	95 (partial agonist)	Template:Abbr
σ1	>1,000	Template:Abbr	Template:Abbr
GABAA	200	>30,000	>10,000
NMDA	0.66 - 3,470a	Template:Abbr	Template:Abbr
5-HT1A	>1,000	Template:Abbr	Template:Abbr
5-HT1B	>1,000	Template:Abbr	Template:Abbr
5-HT1D	>1,000	Template:Abbr	Template:Abbr
5-HT2	2,000	1,000	1,700
5-HT6	>1,000	Template:Abbr	Template:Abbr
5-HT7	>1,000	Template:Abbr	Template:Abbr
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	Template:Abbr	Template:Abbr
Kir3.2	12,400b	Template:Abbr	Template:Abbr
Kir3.1/3.4	6,500b	Template:Abbr	Template:Abbr
hERG	6,300	20,000	5,710
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:<ref name = NPP2002 /><ref name="PMID15225731" /><ref name = Sa2005/><ref name = part2 />

Atomoxetine inhibits the presynaptic norepinephrine 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, where dopamine transporter (DAT) expression is minimal.<ref name = Sa2005/> In rats, atomoxetine increased prefrontal cortex catecholamine concentrations without altering dopamine levels in the striatum or nucleus accumbens; in contrast, methylphenidate, a dopamine reuptake inhibitor, was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree.<ref name="HodgkinsShawMcCarthy2012">Template:Cite journal</ref><ref name = NPP2002>Template:Cite journal</ref> In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.<ref name = PMID20403082>Template:Cite journal</ref>

Atomoxetine's status as a serotonin transporter (SERT) inhibitor at clinical doses in humans is uncertain. A PET imaging study on rhesus monkeys found that atomoxetine occupied >90% and >85% of neural NET and SERT, respectively.<ref name="DingNaganawa2014">Template:Cite journal</ref> However, both mouse and rat microdialysis studies have failed to find an increase in extracellular serotonin in the prefrontal cortex following acute or chronic atomoxetine treatment.<ref name = NPP2002/><ref name = PMID20403082/> Supporting atomoxetine's selectivity, a human study found no effects on platelet serotonin uptake (a marker of SERT inhibition) and inhibition of the pressor effects of tyramine (a marker of NET inhibition).<ref>Template:Cite journal</ref>

Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations.<ref name = PMID20423340>Template:Cite journal</ref><ref name = PMID28167075>Template:Cite journal</ref> It causes a use-dependent open-channel block and its binding site overlaps with the Mg²⁺ binding site.<ref name = PMID20423340/><ref name = PMID28167075/> Atomoxetine's ability to increase prefrontal cortex firing rate in anesthetized rats could not be blocked by D₁ or α₁-adrenergic receptor antagonists, but could be potentiated by NMDA or an α₂-adrenergic receptor antagonist, suggesting a glutaminergic mechanism.<ref>Template:Cite journal</ref> In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels.<ref name = PMID24348020>Template:Cite journal</ref> Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Atomoxetine also reversibly inhibits GIRK currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner.<ref name = PMID20393461>Template:Cite journal</ref> K_ir3.1/3.2 ion channels are opened downstream of M₂, α₂, D₂, and A₁ stimulation, as well as other G_i-coupled receptors.<ref name = PMID20393461/> Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers.<ref name = PMID20393461/> 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 for opioid receptors, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors.<ref name="PMID15225731">Template:Cite journal</ref> It is not known whether this action at the kappa-opioid receptor leads to CNS-related adverse effects.

Pharmacokinetics

Orally administered atomoxetine is rapidly and completely absorbed.<ref name = Sa2005/> First-pass metabolism by the liver is dependent on CYP2D6 activity, resulting in an absolute bioavailability of 63% for extensive metabolizers and 94% for poor metabolizers.<ref name = Sa2005/> Maximum plasma concentration is reached in 1–2 hours.<ref name = Sa2005/> If taken with food, the maximum plasma concentration decreases by 10–40% and delays the t_max by 3 hours.<ref name = Sa2005/> Drugs affecting gastric pH have no effect on oral bioavailability.<ref name="Strattera FDA label" />

Following intravenous delivery, atomoxetine has a volume of distribution of 0.85 L/kg (indicating distribution primarily in total body water), with limited partitioning into red blood cells.<ref name = Sa2005/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is highly bound to plasma proteins (98.7%), mainly albumin, along with α₁-acid glycoprotein (77%) and IgG (15%).<ref name = Sa2005/><ref name = part2/> Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.<ref name = Sa2005/>

The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours.<ref name = Sa2005/><ref name = PMID26314574>Template:Cite journal</ref> As atomoxetine is metabolized by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolizers.<ref name = PMID26314574/> Among CYP2D6 extensive metabolizers, the half-life of atomoxetine averaged 5.34 hours and the half-life of the active metabolite N-desmethylatomoxetine was 8.9 hours.<ref name = Sa2005/><ref name="sa2003">Template:Cite journal</ref> By contrast, among CYP2D6 poor metabolizers the half-life of atomoxetine averaged 20.0 hours and the half-life of N-desmethylatomoxetine averaged 33.3 hours.<ref name = Sa2005/><ref name="sa2003"/> Steady-state levels of atomoxetine are typically achieved at or around day 10 of regular dosing, with trough plasma concentrations (C_trough) residing around 30–40°ng/mL; however, both the time to steady-state levels and C_trough are expected to vary based on a patient's CYP2D6 profile.<ref>Template:Cite journal</ref><ref>Template:Cite encyclopedia</ref>

Atomoxetine, N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhibition of CYP1A2 and CYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6 and 17 μmol/L.Template:Citation needed Plasma concentrations of 4-hydroxyatomoxetine and N-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.<ref name="Strattera FDA label" />

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.<ref name = Sa2005/> 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.<ref name = Sa2005/> CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.<ref name = Sa2005/>

File:Atomoxetine metabolism.png

Major metabolites of atomoxetine in humans.<ref name = Sa2005/>

Pharmacogenomics

Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higher area-under-the-curve (AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolizers.<ref name = Sa2005/>

Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolizers.<ref name = Sa2005/>

Chemistry

Atomoxetine, or (−)-methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropylamine, is a white, granular powder that is highly soluble in water.

• Strattera 60mg capsule back.jpg

  Strattera 60-mg capsule back

• Lilly Strattera 60mg Capsule.jpg

  Strattera 60-mg capsule front with Lilly logo

Synthesis

File:Atomoxetine-synthesis.png

Original synthesis of atomoxetine, as patented by Eli Lilly and Company<ref>Template:Cite patent</ref><ref>Template:Cite patent</ref>

Detection in biological fluids

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.<ref>Template:Cite book</ref>

History

Atomoxetine is manufactured, marketed, and sold in the United States as the hydrochloride salt (atomoxetine HCl) under the brand name Strattera by Eli Lilly and Company, the original patent-filing company and current U.S. patent owner. Atomoxetine was initially intended to be developed 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.<ref name="orangeBook">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="w934">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.<ref>Template:Cite news</ref> 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."<ref>Template:Cite news</ref>

In 2017 the FDA approved the generic production of atomoxetine by four pharmaceutical companies.<ref name="FDA PR">Template:Cite press release</ref>

Society and culture

The drug was originally known as tomoxetine. It was renamed to avoid medication errors, as the name may be confused with tamoxifen.<ref>Template:Cite journal</ref>

Brand names

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 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, a generic version was approved in the United States.<ref name="FDA PR" />

Research

There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, particularly in cases with concomitant ADHD.<ref name="NHMH">Template:Cite bookTemplate:Page needed</ref>

Atomoxetine may be used in those with ADHD and bipolar disorder although such use has not been well established.<ref>Template:Cite journal</ref> Some benefit has also been seen in people with ADHD and autism.<ref>Template:Cite book</ref> 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<ref>Template:Cite journal</ref> or methamphetamine dependence.<ref>Template:Cite journal</ref>

Further reading

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