Chemistry:Atomoxetine

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Atomoxetine, sold under the brand name Strattera,[1] is a selective norepinephrine reuptake inhibitor (NRI) medication used to treat attention deficit hyperactivity disorder (ADHD)[2] and, to a lesser extent, cognitive disengagement syndrome (CDS).[3][4][5] It may be used alone or along with psychostimulant medication.[6][7] It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time,[8] and emotional self-regulation.[9][10] Use of atomoxetine is only recommended for those who are at least six years old.[2] It is taken orally.[2] The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.[11][12][13][14]

Common side effects of atomoxetine include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness.[2] Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression.[2][15] 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.[16][17]

It was approved for medical use in the United States in 2002.[2] In 2023, it was the 161st most commonly prescribed medication in the United States, with more than 3 million prescriptions.[18][19]


Medical uses

Attention deficit hyperactivity disorder

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD).[20] It is approved for use in children, adolescents, and adults.[20] However, its efficacy has not been studied in children under six years old.[21] One of the primary differences with the standard stimulant treatments for ADHD is that it has no known misuse potential.[21][22] 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.[11][12][13][14] The benefits of atomoxetine against ADHD symptoms are dose-dependent until a plateau is reached.[23]

While its efficacy may be less than that of lisdexamfetamine,[24] there is some evidence supporting its use in combination with stimulants.[6] 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;[25][26] 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.[27]

Atomoxetine is thought to alleviate ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine levels in the prefrontal cortex,[28] sharing 70–80% of the brain regions with stimulants in its produced effects.[29]

The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent.[30][31][32] A further 2 to 4 weeks may be required for the full therapeutic effects to be seen.[33][31] Incrementally increasing response may occur up to 1 year or longer.[32][34] The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg.[20]

Other uses

Cognitive disengagement syndrome

Atomoxetine may be used to treat cognitive disengagement syndrome (CDS),[4] as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment.[4][3][5] In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate.[35][36][37][38]

Nocturnal enuresis

Atomoxetine has been studied in the treatment of nocturnal enuresis in children and is effective for this indication.[39][40][41][42]

Excessive sleepiness

Atomoxetine has wakefulness-promoting effects and is used off-label in the treatment of excessive sleepiness in for instance narcolepsy.[43][44][45][46][47]

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).[48][49] It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition,[50] lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome.[48] A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects.[51] Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid hemorrhage in a case report.[49][52]

Available forms

Atomoxetine is available in the form of oral capsules (10, 18, 25, 40, 60, 80, or 100 mg) and in an oral solution (4 mg/mL).[53][54][55] It is taken once or twice daily.[56][57]

Contraindications

Contraindications of atomoxetine include:[56][21][58]

However, the FDA label states that in the case of cardiovascular disease, atomoxetine is only contraindicated in the case of severe cardiovascular disease.[56] However, it states that atomoxetine should be used with caution in people with cardiovascular disease.[56] 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.[56]

A precaution or relative contraindication is concomitant use of strong CYP2D6 inhibitors, which may necessitate atomoxetine dose adjustment.[56]

Side effects

Common side effects include abdominal pain, decreased appetite, nausea, erectile dysfunction, feeling tired, dizziness,[2] and urinary retention.[59] Atomoxetine has been found to modestly increase heart rate and blood pressure.[60][61][62] 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.[63][64] The drug can produce insomnia as a side effect, especially in CYP2D6 poor metabolizers,[60][57][65] but has less overall risk of insomnia than methylphenidate or amphetamines.[57][66][67]

As of 2019, safety in pregnancy and breastfeeding is not clear;[16] a 2018 review stated that, "because of lack of data, the treating physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy."[17]

Serious side effects may include angioedema, liver problems, psychosis, heart problems, suicide, and aggression.[2][15] Atomoxetine does not appear to increase the risk of stroke in adults[68] nor the risk of sudden death.[62] 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.[56] The drug can dramatically increase blood pressure in people with central autonomic failure, even at very low doses.[69] Rarely, atomoxetine can cause drug-induced liver injury or liver failure.[70][56]

Atomoxetine may increase the likelihood of aggression and hostility in children with ADHD, although such events are rare.[71] The U.S. Food and Drug Administration (FDA) has issued a black box warning for suicidal behavior/ideation.[72] Similar warnings have been issued in Australia.[21][73] Unlike stimulant medications, atomoxetine does not have misuse liability or the potential to cause withdrawal effects upon abrupt discontinuation.[21][22][74]

Atomoxetine has been found to directly inhibit hERG potassium currents with an IC50 of 6,300 nM, which has the potential to cause arrhythmia.[75][76] No substantial QTc interval changes were observed in a clinical study of atomoxetine in CYP2D6 poor metabolizers.[56][77] However, small changes could not be ruled out, and there was a slight but significant increase in QTc interval with higher atomoxetine concentrations.[56][77] 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.[75]

Unlike α2-adrenergic receptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant withdrawal symptoms being observed.[21]

Overdose

Atomoxetine can lead to cardiac complications, with severe overdose requiring intensive medical care to avoid death.[78]

Interactions

Atomoxetine is a substrate for CYP2D6.[56] 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.[79][75][80][54] Bupropion increased atomoxetine exposure by 5.1-fold and decreased 4-hydroxyatomoxetine-O-glucuronide exposure by 1.5-fold.[79] Similarly, paroxetine increased atomoxetine steady-state peak levels by 3.5-fold, total exposure (over 12 hours) by 6.5-fold, and elimination half-life by 2.5-fold.[57] Findings were analogous for fluoxetine and quinidine.[56][54] CYP2D6 inhibitors do not appear to affect atomoxetine metabolism in CYP2D6 poor metabolizers.[56][57] Dosage adjustment of atomoxetine may be necessary in people taking strong CYP2D6 inhibitors.[56]

Atomoxetine does not show clinically important inhibition or induction of cytochrome P450 (CYP450) enzymes including CYP1A2, CYP3A, CYP2D6, and CYP2C9.[56][81] It did not affect the pharmacokinetics of the CYP2D6 substrate desipramine, whereas it increased exposure to the CYP3A4 substrate midazolam by only 15%.[56][81] Atomoxetine is a moderate to potent inhibitor of P-glycoprotein.[54]

Other notable drug interactions include:

Drugs affecting gastric pH have no effect on the bioavailability or pharmacokinetics of atomoxetine.[20][54]

Atomoxetine prevents norepinephrine release induced by amphetamines and has been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.[83][84][85]

Pharmacology

Pharmacodynamics

Site ATX 4-OH-ATX N-DM-ATX
SERT 77 43 ND
NET 5 3 92
DAT 1,451 ND ND
MOR >1,000[86] 422 (antagonist?) ND
DOR ND 300 (antagonist?) ND
KOR >1,000?[86] 95 (partial agonist) ND
σ1 >1,000 ND ND
GABAA 200 >30,000 >10,000
NMDA 0.66–3,470a ND ND
5-HT1A >1,000 ND ND
5-HT1B >1,000 ND ND
5-HT1D >1,000 ND ND
5-HT2 2,000 1,000 1,700
5-HT6 >1,000 ND ND
5-HT7 >1,000 ND ND
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 ND ND
Kir3.2 12,400b ND ND
Kir3.1/3.4 6,500b ND ND
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: [87][86][81][82]

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.[81] 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 (DRI), was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree.[88][87] In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.[89] Atomoxetine is selective for the NET over many other targets.[57][90][91]

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.[92] 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.[87][89] Supporting atomoxetine's selectivity, human studies found no effects on platelet serotonin uptake (a marker of SERT inhibition) but robust inhibition of the pressor effects of tyramine (a marker of NET inhibition).[93][94] Subsequently, atomoxetine was found to dose-dependently inhibit the NET from low doses in humans but did not inhibit the SERT to a clinically significant degree.[94][95] Conversely, venlafaxine robustly inhibited the SERT but only inhibited the NET at high doses.[94]

Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations (IC50 = ~3,000 nM).[96][97] It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site.[96][97] 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.[98] In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels.[99] Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD.[100][101]

Atomoxetine also reversibly inhibits G protein-coupled inwardly rectifying potassium channel (GIRK) currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner.[102] Kir3.1/3.2 ion channels are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors.[102] Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers.[102] It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.

It has been found to inhibit voltage-gated sodium channels.[103][104]

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 the μ-opioid receptor (MOR) and as a partial agonist at the κ-opioid receptor (KOR).[86] The affinities (IC50) of 4-hydroxyatomoxetine were 164 nM for the MOR, 88 nM for the KOR, 1,490 nM for the δ-opioid receptor (DOR), and >5,000 nM for the nociceptin receptor (ORL-1).[86] Atomoxetine itself showed dramatically lower affinities (e.g., 25- to 50-fold).[86] It is not known whether the actions of 4-hydroxyatomoxetine at the opioid receptors leads to CNS-related adverse effects with atomoxetine.[86]

Atomoxetine does not alter locomotor activity in rodents, in contrast to stimulants like amphetamine.[22] In addition, atomoxetine does not produce self-administration in monkeys, also in contrast to stimulants like amphetamine.[22] The drug does not produce stimulant-like effects, euphoria, or reinforcing effects in humans, instead increasing negative and unpleasant ratings at the highest assessed doses.[22]

Atomoxetine has been found to increase cortisol levels in humans.[105][106][107]

Pharmacokinetics

Mean circulating atomoxetine levels (ng/mL) with 50 mg atomoxetine as either oral solution or oral capsules in Japanese adults.[108][109]

Absorption

The absorption of atomoxetine with oral administration is rapid and complete.[81][57][54][56] The drug's absolute bioavailability is 63 to 94%.[81][56] This is moderated by first-pass metabolism and CYP2D6 status, with poor metabolizers having a bioavailability of 94% and extensive metabolizers having a bioavailability of 63%.[81][56] Extensive metabolizers are considered to have normal CYP2D6 activity and constitute >90% of people, while poor metabolizers constitute a small minority of up to 7%.[81][60][57][56] The bioavailability of atomoxetine is not different between capsule and solution forms.[54]

The time to peak levels of atomoxetine is 1 to 2 hours.[56][57] It has been reported that the time to peak levels was 1.0 hours in CYP2D6 extensive metabolizers and 2.5 hours in CYP2D6 poor metabolizers.[54] Taking atomoxetine with food does not affect its bioavailability or total exposure but decreases peak levels by 9% with a typical meal and 37% with a standard high-fat breakfast.[81][56] In addition, food delays the time to peak levels by 3 hours.[81][56] Atomoxetine exposure increases proportionally with higher doses over a range of 10 to 120 mg orally.[57][81][54] Exposure to atomoxetine is proportional to body weight, and hence weight-normalizing dosing is required to produce equivalent exposure.[81][54]

In CYP2D6 poor metabolizers, atomoxetine peak levels are 5- to 6-fold higher and total exposure is 8- to 10-fold higher than in CYP2D6 extensive metabolizers.[56][110][54][111] Similarly, in Asian adults homozygous for the hypoactive CYP2D6*10 allele, atomoxetine peak levels were about 1.5-fold higher and total exposure 2-fold higher compared to extensive metabolizers.[81][54][111] There is little accumulation of atomoxetine with repeated administration in CYP2D6 extensive metabolizers, but significant accumulation in CYP2D6 poor metabolizers.[81][111] The pharmacokinetics of atomoxetine, for instance elimination half-life, volume of distribution, and clearance, are similar with a single dose versus at steady state.[57]

Distribution

Atomoxetine is well-distributed and its volume of distribution is 0.85 to 1.02 L/kg in CYP2D6 extensive metabolizers and 2.25 L/kg in CYP2D6 poor metabolizers, with its distribution being equivalent to total body water.[81][57][110][56] Atomoxetine and its metabolites show only limited partitioning into red blood cells.[81] Atomoxetine crosses the blood–brain barrier, with this appearing to be due primarily to passive diffusion rather than active transport.[54] The drug is not a substrate of P-glycoprotein.[54] Animal studies have found that atomoxetine and/or its metabolites can cross the placenta, but fetal exposure was substantially lower than maternal exposure.[81] Similarly, only a small amount of atomoxetine and/or metabolites were excreted in milk in animals.[81]

Atomoxetine shows high plasma protein binding of 98.7% and is primarily bound to albumin and to a lesser extent to α1-acid glycoprotein and immunoglobulin G (IgG).[81][57][54][56][82] Atomoxetine's limitedly active metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, whereas its active metabolite 4-hydroxyatomoxetine shows plasma protein binding of 66.6%, which is substantially less than that of atomoxetine itself.[81][54]

Metabolism

Atomoxetine is primarily metabolized via oxidative metabolism.[81][56] The three major metabolic pathways include aromatic ring hydroxylation mainly by CYP2D6 but also other cytochrome P450 enzymes into 4-hydroxyatomoxetine, benzylic hydroxylation by an unspecified enzyme into 2-hydroxymethylatomoxetine, and N-demethylation by CYP2C19 into N-desmethylatomoxetine.[81][54][111] In addition, N-desmethylatomoxetine undergoes hydroxylation by CYP2D6 into N-desmethyl-4-hydroxyatomoxetine.[81] The hydroxylated metabolites of atomoxetine undergo glucuronidation via UDP-glucuronyltransferase (UGT) enzymes to form glucuronide conjugates.[81][54][56]

As previously described, first-pass metabolism of atomoxetine is substantially greater, bioavailability is lower, peak levels and total exposure are much greater, and elimination half-life is much longer in CYP2D6 poor metabolizers than in extensive metabolizers.[56][81][111] The overall metabolism of atomoxetine is similar regardless of CYP2D6 status.[81][57][110] In addition, 4-hydroxyatomoxetine remains the major metabolite of atomoxetine independently of CYP2D6 status.[81][57] But the quantitative amounts of formed atomoxetine metabolites and their rates of formation are substantially different depending on CYP2D6 status.[81][110] Studies with radiolabeled atomoxetine have shown that peak levels of radioactivity are essentially the same between CYP2D6 extensive metabolizers and CYP2D6 poor metabolizers.[81] However, total exposure of radioactivity was larger and elimination half-life of radioactivity was longer (62 hours vs. 18 hours) in CYP2D6 poor metabolizers versus CYP2D6 extensive metabolizers.[81] Circulating 4-hydroxyatomoxetine levels are about 1% of those of circulating atomoxetine levels in CYP2D6 extensive metabolizers and about 0.1% of those of circulating atomoxetine levels in CYP2D6 poor metabolizers.[56][57][54] Similarly, N-desmethylatomoxetine circulates at much lower levels than atomoxetine, about 5% of those of atomoxetine in CYP2D6 extensive metabolizers and 45% of those of atomoxetine in CYP2D6 poor metabolizers.[56][57][54]

4-Hydroxyatomoxetine shows similar affinity for the norepinephrine transporter (NET) as atomoxetine but much higher affinity for the serotonin transporter (SERT) in comparison (with SERT affinity ~14-fold lower than NET affinity), whereas N-desmethylatomoxetine shows much lower affinity for the monoamine transporters (MATs) than atomoxetine and 4-hydroxyatomoxetine (with NET affinity ~20-fold lower than that of atomoxetine).[81][57][54][82] Despite differences in atomoxetine metabolism, CYP2D6 status has been said in literature reviews to not affect the overall tolerability and safety of atomoxetine.[81][60][54] However, poor metabolizers did show greater heart rate increase (+9.4–11 bpm vs. +5.0–7.5 bpm), blood pressure increase (4.21 mm Hg vs. 2.13 mm Hg systolic and 2.75 mg Hg vs. 2.40 mm Hg diastolic), and more weight loss (–1.2 kg vs. +0.8 mg) than extensive metabolizers.[56][81][54][111] In addition, various side effects, including insomnia, sedation, weight loss, constipation, dry mouth, erectile dysfunction, excessive sweating, and urinary retention, among others, have been found to be around twice as frequent in poor metabolizers relative to extensive metabolizers.[56][60][54][111] The same was true for discontinuation rates (11.2% vs. 6.3%).[56] In terms of dosage adjustment for CYP2D6 poor metabolizers or those taking strong CYP2D6 inhibitors, the Food and Drug Administration (FDA) label says that this may be necessary and provides directions for this,[56] whereas literature reviews state that it is not considered necessary based on clinical trial experience.[81][57]

Major metabolites of atomoxetine in humans.[81]

Elimination

Atomoxetine and its metabolites are eliminated mainly via excretion into urine.[81] Less than 3% of atomoxetine is excreted unchanged in urine regardless of CYP2D6 status, indicating extensive metabolism.[56][81][57][112] In CYP2D6 extensive metabolizers, who are considered to have normal CYP2D6 activity, more than 96% of a dose of radiolabeled atomoxetine is excreted in urine within 24 hours and 1 to 2% is excreted in feces.[81][110][112][54] Conversely, in CYP2D6 poor metabolizers, excretion is slower, with only 27% excreted after 24 hours, a majority of radioactivity excreted within 72 hours, and ~144 hours required for full excretion.[81][112][54] In addition, only 80% of radioactivity is excreted in urine while 13 to 22% is excreted in feces in CYP2D6 poor metabolizers.[81][110] The major excreted metabolite of atomoxetine is 4-hydroxyatomoxetine glucuronide, which accounts for >80% of the dose in urine but <17% of the dose in feces.[56][57] The fractions excreted in urine as 4-hydroxyatomoxetine and 4-hydroxyatomoxetine glucuronide account for 86% of a dose in CYP2D6 extensive metabolizers, but only 40% in CYP2D6 poor metabolizers.[81] CYP2D6 poor metabolizers excrete greater amounts of minor atomoxetine metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates, than extensive metabolizers.[81]

The elimination half-life of atomoxetine is 4.5 to 5.3 hours in CYP2D6 extensive metabolizers.[56][111][113] However, in CYP2D6 poor metabolizers, the half-life of atomoxetine is 19 to 21.6 hours, or about 4-fold longer in comparison.[56][110][111][113] In CYP2D6 extensive metabolizers, the half-lives of 4-hydroxyatomoxetine and N-desmethylatomoxetine are similar at around 6 to 8 hours, whereas in CYP2D6 poor metabolizers, the half-life of N-desmethylatomoxetine is much longer at around 33 to 40 hours.[56][81][113] Atomoxetine levels in cerebrospinal fluid (CSF) with atomoxetine at a dosage of 80 mg/day were 6.6 ng/mL at 8 hours post-dose and 1.4 ng/mL at 24 hours post-dose following 2 weeks of administration.[54]

Chemistry

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

  • Strattera 60-mg capsule back
    Strattera 60-mg capsule back
  • Strattera 60-mg capsule front with Lilly logo
    Strattera 60-mg capsule front with Lilly logo

Synthesis

Original synthesis of atomoxetine salt, as patented by Eli Lilly and Company[114][115]

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.[116]

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.[117] 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.[118] On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.[119] 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."[120] In 2017 the FDA approved the generic production of atomoxetine by four pharmaceutical companies.[121]

Society and culture

Names

Atomoxetine was originally known as tomoxetine. It was renamed to avoid medication errors, as the name may be confused with tamoxifen.[122]

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, a generic version was approved in the United States.[121]

Atomoxetine has no risk of misuse and is not a controlled substance.[22][57]

Research

Besides treatment of ADHD, atomoxetine was under formal development by Eli Lilly and Company for the treatment of major depressive disorder, Alzheimer's disease, and Parkinson's disease.[123] However, development for these indications was discontinued.[123] The drug reached phase 3 clinical trials for treatment of Parkinson's disease prior to being discontinued.[123] Though not approved for depression, atomoxetine has been studied and used off-label in the treatment of this condition, for instance as an adjunct to selective serotonin reuptake inhibitors (SSRIs) and to treat residual symptoms such as fatigue, but data are limited.[124][125][126][127][128][129] It has also been studied and used to treat comorbid depression in people with ADHD.[130][131][132]

Atomoxetine has been studied in the treatment of social anxiety disorder, with mixed findings.[133][134][135][136][137] The drug has been found to reduce anxiety symptoms in children and adolescents with ADHD and comorbid anxiety disorders.[138]

Atomoxetine may be used in those with ADHD and bipolar disorder although such use has not been well established.[139] Some benefit has also been seen in people with ADHD and autism.[140] 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[141] or methamphetamine dependence.[142]

Atomoxetine has been studied and used in the treatment of orthostatic hypotension.[143][144][145] It has been reported to be more effective than midodrine.[146][147] The drug synergistically increased blood pressure in combination with pyridostigmine.[148] While acutely effective however, tachyphylaxis has been found to occur with continuous administration of atomoxetine.[143][144] The reasons for this tolerance are unclear.[143]

Though development for Alzheimer's disease was discontinued, perhaps due to negative trial findings, there has been continued interest in atomoxetine in the potential treatment of this disease as of 2025.[108][149] It has also been studied to treat mild cognitive impairment or prodromal Alzheimer's disease.[150]

Atomoxetine is being studied for treatment of sleep apnea in combination with various other drugs including oxybutynin or aroxybutynin,[151][152][153][154] trazodone,[155][156] antimineralocorticoids like spironolactone,[157][158] an orexin receptor antagonist,[159] pimavanserin,[160] acetazolamide,[161] dronabinol (Δ9-tetrahydrocannabinol; THC),[162] fesoterodine,[163] and zolpidem.[164]

Atomoxetine has been studied for reducing appetite and promoting weight loss in people with obesity, with mixed results.[165][166]

References

  1. ↑ "STRATTERA® (atomoxetine capsules) to be discontinued as of March 2023". 3 March 2023. https://www.caddra.ca/treatment-update-strattera-atomoxetine-capsules-to-be-discontinued-as-of-march-2023-2/. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 "Atomoxetine Hydrochloride Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/atomoxetine-hydrochloride.html. 
  3. ↑ 4.0 4.1 4.2 "Report of a Work Group on Sluggish Cognitive Tempo: Key Research Directions and a Consensus Change in Terminology to Cognitive Disengagement Syndrome". Journal of the American Academy of Child and Adolescent Psychiatry 62 (6): 629–645. June 2023. doi:10.1016/j.jaac.2022.07.821. PMID 36007816. 
  4. ↑ 5.0 5.1 "Atomoxetine improved attention in children and adolescents with attention-deficit/hyperactivity disorder and dyslexia in a 16 week, acute, randomized, double-blind trial". Journal of Child and Adolescent Psychopharmacology 23 (9): 605–613. November 2013. doi:10.1089/cap.2013.0054. PMID 24206099. 
  5. ↑ 6.0 6.1 "A systematic review of combination therapy with stimulants and atomoxetine for attention-deficit/hyperactivity disorder, including patient characteristics, treatment strategies, effectiveness, and tolerability". Journal of Child and Adolescent Psychopharmacology 23 (3): 179–193. April 2013. doi:10.1089/cap.2012.0093. PMID 23560600. 
  6. ↑ "Parent's Medication Guide: ADHD". American Psychiatric Association & American Academy of Child and Adolescent Psychiatry (AACAP). June 2013. https://www.psychiatry.org/patients-families/adhd/what-is-adhd. "Though not FDA-approved for combined treatment, atomoxetine (Strattera) is sometimes used in conjunction with stimulants as an off-label combination therapy." 
  7. ↑ "The effects of chronic administration of stimulant and non-stimulant medications on executive functions in ADHD: A systematic review and meta-analysis". Neuroscience and Biobehavioral Reviews 162. July 2024. doi:10.1016/j.neubiorev.2024.105703. PMID 38718988. https://kclpure.kcl.ac.uk/portal/en/publications/69dc26fe-1517-438e-9cd7-6788fc396dc9. 
  8. ↑ "The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder". Neuroscience and Biobehavioral Reviews 128: 789–818. September 2021. doi:10.1016/j.neubiorev.2021.01.022. PMID 33549739. Bibcode: 2021NBRev.128..789F. 
  9. ↑ "Executive function assessment and adult attention-deficit/hyperactivity disorder: tasks versus ratings on the Barkley deficits in executive functioning scale". Psychological Assessment 26 (4): 1095–1105. December 2014. doi:10.1037/pas0000006. PMID 24885846. 
  10. ↑ 11.0 11.1 "Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis". BMC Psychiatry 11. November 2011. doi:10.1186/1471-244X-11-176. PMID 22074258. 
  11. ↑ 12.0 12.1 "Comparative efficacy of methylphenidate and atomoxetine in the treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review and meta-analysis". Medical Journal of the Islamic Republic of Iran 30: 325. 10 February 2016. PMID 27390695. 
  12. ↑ 13.0 13.1 "Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis". Journal of Attention Disorders 15 (8): 674–683. November 2011. doi:10.1177/1087054710379737. PMID 20837981. http://journals.sagepub.com/doi/10.1177/1087054710379737. Retrieved 7 December 2023. 
  13. ↑ 14.0 14.1 "A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients". Journal of Psychopharmacology 30 (5): 444–458. May 2016. doi:10.1177/0269881116636105. PMID 27005307. http://journals.sagepub.com/doi/10.1177/0269881116636105. Retrieved 7 December 2023. 
  14. ↑ 15.0 15.1 British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 344–345. ISBN 978-0-85711-338-2. 
  15. ↑ 16.0 16.1 "Atomoxetine Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/atomoxetine.html. 
  16. ↑ 17.0 17.1 "Pharmacological Treatment of Attention Deficit Hyperactivity Disorder During Pregnancy and Lactation". Pharmaceutical Research 35 (3). February 2018. doi:10.1007/s11095-017-2323-z. PMID 29411149. 
  17. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  18. ↑ "Atomoxetine Drug Usage Statistics, United States, 2014 - 2023". https://clincalc.com/DrugStats/Drugs/Atomoxetine. 
  19. ↑ 20.0 20.1 20.2 20.3 "Strattera- atomoxetine hydrochloride capsule". Eli Lilly and Company. 29 January 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=309de576-c318-404a-bc15-660c2b1876fb. 
  20. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 "Strattera (atomoxetine hydrochloride)". TGA eBusiness Services. Eli Lilly Australia Pty. Limited. 21 August 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04269-3. 
  21. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 "A review of the abuse potential assessment of atomoxetine: a nonstimulant medication for attention-deficit/hyperactivity disorder". Psychopharmacology (Berl) 226 (2): 189–200. March 2013. doi:10.1007/s00213-013-2986-z. PMID 23397050. 
  22. ↑ "The Dose-Response Relationship of Atomoxetine for the Treatment of Children With ADHD: A Systematic Review and Dose-Response Meta-Analysis of Double-Blind Randomized Placebo-Controlled Trials". J Atten Disord 28 (4): 431–438. February 2024. doi:10.1177/10870547231214988. PMID 38069471. 
  23. ↑ "Comparative efficacy and acceptability of atomoxetine, lisdexamfetamine, bupropion and methylphenidate in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis with focus on bupropion". Journal of Affective Disorders 178: 149–159. June 2015. doi:10.1016/j.jad.2015.03.006. PMID 25813457. 
  24. ↑ "Attention Deficit Hyperactivity Disorder". National Institute of Mental Health (NIMH). https://www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd. 
  25. ↑ "Mental Health Medications". https://www.nimh.nih.gov/health/topics/mental-health-medications. 
  26. ↑ "Effects of stimulants and atomoxetine on emotional lability in adults: A systematic review and meta-analysis". Eur Psychiatry 44: 198–207. July 2017. doi:10.1016/j.eurpsy.2017.05.021. PMID 28646732. https://research-information.bris.ac.uk/en/publications/d9cd6fbb-334c-4d03-896c-1ba5c4eca8e3. 
  27. ↑ "Effects of acute and chronic administration of atomoxetine and methylphenidate on extracellular levels of noradrenaline, dopamine and serotonin in the prefrontal cortex and striatum of mice". Journal of Neurochemistry 114 (1): 259–270. July 2010. doi:10.1111/j.1471-4159.2010.06750.x. PMID 20403082. 
  28. ↑ "Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder". Archives of General Psychiatry 69 (9): 952–961. September 2012. doi:10.1001/archgenpsychiatry.2011.2053. PMID 22945622. 
  29. ↑ "Atomoxetine (Rx) – Strattera". Medscape Reference. WebMD. http://reference.medscape.com/drug/strattera-atomoxetine-342994. 
  30. ↑ 31.0 31.1 "Systematic review of atomoxetine data in childhood and adolescent attention-deficit hyperactivity disorder 2009-2011: focus on clinical efficacy and safety". Journal of Psychopharmacology 28 (3): 204–211. March 2014. doi:10.1177/0269881113478475. PMID 23438503. 
  31. ↑ 32.0 32.1 "A critical appraisal of atomoxetine in the management of ADHD". Therapeutics and Clinical Risk Management 12: 27–39. 2016. doi:10.2147/TCRM.S59270. PMID 26730199. 
  32. ↑ The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. 2012. ISBN 978-0-470-97948-8. 
  33. ↑ "Atomoxetine in patients with ADHD: A clinical and pharmacological review of the onset, trajectory, duration of response and implications for patients". Journal of Psychopharmacology 29 (12): 1221–1230. December 2015. doi:10.1177/0269881115602489. PMID 26349559. 
  34. ↑ "An Open-Label Trial of Methylphenidate Treating Sluggish Cognitive Tempo, Inattention, and Hyperactivity/Impulsivity Symptoms Among 6- to 12-Year-Old ADHD Children: What Are the Predictors of Treatment Response at Home and School?". Journal of Attention Disorders 25 (9): 1321–1330. July 2021. doi:10.1177/1087054720902846. PMID 32064995. 
  35. ↑ "Sluggish Cognitive Tempo as a Possible Predictor of Methylphenidate Response in Children With ADHD: A Randomized Controlled Trial". The Journal of Clinical Psychiatry 79 (2). 2018. doi:10.4088/JCP.17m11553. PMID 29489078. 
  36. ↑ "Attention deficit disorder with and without hyperactivity: clinical response to three dose levels of methylphenidate". Pediatrics 87 (4): 519–531. April 1991. doi:10.1542/peds.87.4.519. PMID 2011430. 
  37. ↑ "Concentration deficit disorder (sluggish cognitive tempo).". Attention-deficit hyperactivity disorder: A handbook for diagnosis and treatment.. The Guilford Press. 2015. pp. 81–115. https://www.peterraabe.ca/docs/SCT_Barkley.pdf. Retrieved 28 February 2024. 
  38. ↑ "Drugs for nocturnal enuresis in children (other than desmopressin and tricyclics)". Cochrane Database Syst Rev 2012 (12). December 2012. doi:10.1002/14651858.CD002238.pub2. PMID 23235587. 
  39. ↑ "Atomoxetine for the treatment of pediatric nocturnal enuresis". J Child Adolesc Psychopharmacol 14 (3): 443–447. 2004. doi:10.1089/cap.2004.14.443. PMID 15650501. 
  40. ↑ "Placebo-controlled study of the effects of atomoxetine on bladder control in children with nocturnal enuresis". J Child Adolesc Psychopharmacol 16 (6): 699–711. December 2006. doi:10.1089/cap.2006.16.699. PMID 17201614. 
  41. ↑ "Atomoxetine ameliorates nocturnal enuresis with subclinical attention-deficit/hyperactivity disorder". Pediatr Int 59 (2): 181–184. February 2017. doi:10.1111/ped.13111. PMID 27501068. 
  42. ↑ "Recent advances in the treatment of narcolepsy". Curr Treat Options Neurol 13 (5): 437–457. October 2011. doi:10.1007/s11940-011-0137-6. PMID 21748548. 
  43. ↑ "A practical guide to the therapy of narcolepsy and hypersomnia syndromes". Neurotherapeutics 9 (4): 739–752. October 2012. doi:10.1007/s13311-012-0150-9. PMID 23065655. 
  44. ↑ "Treatment of disorders of hypersomnolence". Curr Treat Options Neurol 16 (9). September 2014. doi:10.1007/s11940-014-0302-9. PMID 25080137. 
  45. ↑ "Update on therapy for narcolepsy". Curr Treat Options Neurol 17 (5): 347. May 2015. doi:10.1007/s11940-015-0347-4. PMID 25854650. 
  46. ↑ "[Clinical effect of atomoxetine hydrochloride in 66 children with narcolepsy]" (in Chinese). Zhonghua Er Ke Za Zhi 53 (10): 760–764. October 2015. PMID 26758112. 
  47. ↑ 48.0 48.1 "Atomoxetine for individuals with traumatic brain injury". The Journal of Head Trauma Rehabilitation 21 (1): 85–88. 2006. doi:10.1097/00001199-200601000-00010. PMID 16456396. 
  48. ↑ 49.0 49.1 "On the pathophysiology and treatment of akinetic mutism". Neuroscience and Biobehavioral Reviews 112: 270–278. May 2020. doi:10.1016/j.neubiorev.2020.02.006. PMID 32044373. 
  49. ↑ "Emerging Treatment Strategies in Tourette Syndrome". Emerging treatment strategies in Tourette syndrome: what's in the pipeline?. International Review of Neurobiology. 112. 2013. pp. 445–480. doi:10.1016/B978-0-12-411546-0.00015-9. ISBN 978-0-12-411546-0. "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)." 
  50. ↑ "Pharmacotherapy for chronic cognitive impairment in traumatic brain injury". The Cochrane Database of Systematic Reviews (12). December 2015. doi:10.1002/14651858.CD009221.pub2. PMID 26624881. 
  51. ↑ "Treatment of chronic akinetic mutism with atomoxetine: subtraction analysis of brain f-18 fluorodeoxyglucose positron emission tomographic images before and after medication: a case report". Clinical Neuropharmacology 33 (4): 209–211. July 2010. doi:10.1097/WNF.0b013e3181dca948. PMID 20661027. https://ir.ymlib.yonsei.ac.kr/handle/22282913/101391. 
  52. ↑ "The Mechanism, Clinical Efficacy, Safety, and Dosage Regimen of Atomoxetine for ADHD Therapy in Children: A Narrative Review". Front Psychiatry 12. 2021. doi:10.3389/fpsyt.2021.780921. PMID 35222104. "For children and adolescents over 70 kg, the recommended dose is to increase from a daily initiation dose of 40–80 mg, and the maximum total daily dose should not exceed 100 mg in the USA and Europe. It is manufactured in capsules containing 10, 18, 25, 40, 60, 80, or 100 mg of atomoxetine hydrochloride as well as in an oral solution (4 mg/ml) (103).". 
  53. ↑ 54.00 54.01 54.02 54.03 54.04 54.05 54.06 54.07 54.08 54.09 54.10 54.11 54.12 54.13 54.14 54.15 54.16 54.17 54.18 54.19 54.20 54.21 54.22 54.23 54.24 54.25 54.26 "Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition". J Child Adolesc Psychopharmacol 26 (4): 314–326. May 2016. doi:10.1089/cap.2015.0137. PMID 26859445. 
  54. ↑ "Drugs@FDA: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. 
  55. ↑ 56.00 56.01 56.02 56.03 56.04 56.05 56.06 56.07 56.08 56.09 56.10 56.11 56.12 56.13 56.14 56.15 56.16 56.17 56.18 56.19 56.20 56.21 56.22 56.23 56.24 56.25 56.26 56.27 56.28 56.29 56.30 56.31 56.32 56.33 56.34 56.35 56.36 56.37 56.38 56.39 https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021411s050lbl.pdf
  56. ↑ 57.00 57.01 57.02 57.03 57.04 57.05 57.06 57.07 57.08 57.09 57.10 57.11 57.12 57.13 57.14 57.15 57.16 57.17 57.18 57.19 57.20 57.21 "Spotlight on atomoxetine in attention-deficit hyperactivity disorder in children and adolescents". CNS Drugs 24 (1): 85–88. January 2010. doi:10.2165/11203670-000000000-00000. PMID 20030421. 
  57. ↑ "Off-label use of atomoxetine in adults: is it safe?". Ment Illn 4 (2): 96–101. July 2012. doi:10.4081/mi.2012.e19. PMID 25478120. 
  58. ↑ "A review of the adverse effects and safety of noradrenergic antidepressants". Journal of Psychopharmacology 27 (8): 732–739. August 2013. doi:10.1177/0269881113492027. PMID 23784737. "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).". 
  59. ↑ 60.0 60.1 60.2 60.3 60.4 "Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: an integrated analysis of 15 clinical trials". J Psychopharmacol 29 (1): 3–14. January 2015. doi:10.1177/0269881114560183. PMID 25424623. 
  60. ↑ "Cardiovascular Effects of Stimulant and Non-Stimulant Medication for Children and Adolescents with ADHD: A Systematic Review and Meta-Analysis of Trials of Methylphenidate, Amphetamines and Atomoxetine". CNS Drugs 31 (3): 199–215. March 2017. doi:10.1007/s40263-017-0410-7. PMID 28236285. 
  61. ↑ 62.0 62.1 "Cardiovascular effects of methylphenidate, amphetamines and atomoxetine in the treatment of attention-deficit hyperactivity disorder". Drug Saf 33 (10): 821–842. October 2010. doi:10.2165/11536380-000000000-00000. PMID 20812768. 
  62. ↑ "Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects". World Psychiatry 19 (2): 214–232. June 2020. doi:10.1002/wps.20765. PMID 32394557. 
  63. ↑ "Psychiatric drugs given to children and adolescents have been ranked in order of safety". NIHR Evidence. 1 September 2020. doi:10.3310/alert_40795. https://evidence.nihr.ac.uk/alert/psychiatric-drugs-given-to-children-and-adolescents-have-been-ranked-in-order-of-safety/. Retrieved 12 March 2022. 
  64. ↑ "Adult Attention-Deficit/Hyperactivity Disorder (ADHD) and Insomnia: an Update of the Literature". Curr Psychiatry Rep 19 (12). October 2017. doi:10.1007/s11920-017-0860-0. PMID 29086065. https://pure.amsterdamumc.nl/en/publications/0e259ae1-d58c-4034-9cf2-2dc11879f490. 
  65. ↑ "Comparative efficacy and safety of methylphenidate and atomoxetine for attention-deficit hyperactivity disorder in children and adolescents: Meta-analysis based on head-to-head trials". J Clin Exp Neuropsychol 39 (9): 854–865. November 2017. doi:10.1080/13803395.2016.1273320. PMID 28052720. 
  66. ↑ "Effects of atomoxetine and methylphenidate on sleep in children with ADHD". Sleep 29 (12): 1573–1585. December 2006. doi:10.1093/sleep/29.12.1573. PMID 17252888. 
  67. ↑ "Atomoxetine and cerebrovascular outcomes in adults". J Clin Psychopharmacol 29 (5): 453–460. October 2009. doi:10.1097/JCP.0b013e3181b2b828. PMID 19745645. 
  68. ↑ "Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function". Hypertension 50 (1): 47–53. July 2007. doi:10.1161/HYPERTENSIONAHA.107.089961. PMID 17515448. 
  69. ↑ "Hepatic events associated with atomoxetine treatment for attention-deficit hyperactivity disorder". Drug Saf 31 (4): 345–354. 2008. doi:10.2165/00002018-200831040-00008. PMID 18366245. 
  70. ↑ "Meta-analysis of aggression or hostility events in randomized, controlled clinical trials of atomoxetine for ADHD". Biol Psychiatry 61 (5): 713–719. March 2007. doi:10.1016/j.biopsych.2006.05.044. PMID 16996485. 
  71. ↑ "Atomoxetine Hydrochloride capsule [Mylan Pharmaceuticals Inc."]. DailyMed. Mylan Pharmaceuticals Inc.. October 2011. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=bdab7205-d0ff-41c3-8430-2d399dfaa759. 
  72. ↑ "Atomoxetine and suicidality in children and adolescents". Australian Prescriber 4 (5): 166. October 2013. http://www.australianprescriber.com/magazine/36/5/166/9. Retrieved 10 November 2013. 
  73. ↑ "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. February 2004. doi:10.1097/01.jcp.0000104907.75206.c2. PMID 14709944. 
  74. ↑ 75.0 75.1 75.2 "Cardiovascular side effects of atomoxetine and its interactions with inhibitors of the cytochrome p450 system". Case Reports in Medicine 2011. 2011. doi:10.1155/2011/952584. PMID 21765848. 
  75. ↑ "Selective noradrenaline reuptake inhibitor atomoxetine directly blocks hERG currents". British Journal of Pharmacology 156 (2): 226–236. January 2009. doi:10.1111/j.1476-5381.2008.00018.x. PMID 19154426. 
  76. ↑ 77.0 77.1 "Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers". Br J Clin Pharmacol 75 (2): 538–549. February 2013. doi:10.1111/j.1365-2125.2012.04382.x. PMID 22803597. 
  77. ↑ "Refractory cardiogenic shock due to atomoxetine overdose rescued by venoarterial extracorporeal membrane oxygenation: A case report". Acute Medicine & Surgery 11 (1). 29 August 2024. doi:10.1002/ams2.70001. PMID 39211522. 
  78. ↑ 79.0 79.1 "Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers". Journal of Pharmacy & Pharmaceutical Sciences 19 (2): 198–207. April–June 2016. doi:10.18433/j3h03r. PMID 27518170. 
  79. ↑ "Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics". Journal of Clinical Pharmacology 42 (11): 1219–1227. November 2002. doi:10.1177/009127002762491307. PMID 12412820. 
  80. ↑ 81.00 81.01 81.02 81.03 81.04 81.05 81.06 81.07 81.08 81.09 81.10 81.11 81.12 81.13 81.14 81.15 81.16 81.17 81.18 81.19 81.20 81.21 81.22 81.23 81.24 81.25 81.26 81.27 81.28 81.29 81.30 81.31 81.32 81.33 81.34 81.35 81.36 81.37 81.38 81.39 81.40 81.41 81.42 81.43 "Clinical pharmacokinetics of atomoxetine". Clinical Pharmacokinetics 44 (6): 571–590. 2005. doi:10.2165/00003088-200544060-00002. PMID 15910008. 
  81. ↑ 82.0 82.1 82.2 82.3 "21-411 Strattera Clinical Pharmacology Biopharmaceutics Review Part 2". https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-411_Strattera_biopharmr_P2.pdf. 
  82. ↑ "A systematic review of combination therapy with stimulants and atomoxetine for attention-deficit/hyperactivity disorder, including patient characteristics, treatment strategies, effectiveness, and tolerability". J Child Adolesc Psychopharmacol 23 (3): 179–193. April 2013. doi:10.1089/cap.2012.0093. PMID 23560600. 
  83. ↑ "ADHD: current and future therapeutics". Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment. Current Topics in Behavioral Neurosciences. 9. 2012. pp. 361–390. doi:10.1007/7854_2011_125. ISBN 978-3-642-24611-1. "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)." 
  84. ↑ "Atomoxetine attenuates dextroamphetamine effects in humans". Am J Drug Alcohol Abuse 35 (6): 412–416. 2009. doi:10.3109/00952990903383961. PMID 20014909. 
  85. ↑ 86.0 86.1 86.2 86.3 86.4 86.5 86.6 "Synthesis and biological evaluation of the major metabolite of atomoxetine: elucidation of a partial kappa-opioid agonist effect". Bioorganic & Medicinal Chemistry Letters 14 (15): 4083–4085. August 2004. doi:10.1016/j.bmcl.2004.05.018. PMID 15225731. 
  86. ↑ 87.0 87.1 87.2 "Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder". Neuropsychopharmacology 27 (5): 699–711. November 2002. doi:10.1016/S0893-133X(02)00346-9. PMID 12431845. 
  87. ↑ "The pharmacology and clinical outcomes of amphetamines to treat ADHD: does composition matter?". CNS Drugs 26 (3): 245–268. March 2012. doi:10.2165/11599630-000000000-00000. PMID 22329564. 
  88. ↑ 89.0 89.1 "Effects of acute and chronic administration of atomoxetine and methylphenidate on extracellular levels of noradrenaline, dopamine and serotonin in the prefrontal cortex and striatum of mice". Journal of Neurochemistry 114 (1): 259–270. July 2010. doi:10.1111/j.1471-4159.2010.06750.x. PMID 20403082. 
  89. ↑ "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology (Berl) 114 (4): 559–565. May 1994. doi:10.1007/BF02244985. PMID 7855217. 
  90. ↑ "A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain". J Pharmacol Exp Ther 222 (1): 61–65. July 1982. doi:10.1016/S0022-3565(25)33153-8. PMID 6123593. 
  91. ↑ "Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD". NeuroImage 86: 164–171. February 2014. doi:10.1016/j.neuroimage.2013.08.001. PMID 23933039. "The noradrenergic action also exerts an important clinical effect in different antidepressant classes such as desipramine and nortriptyline (tricyclics, prevalent noradrenergic effect), reboxetine and atomoxetine (relatively pure noradrenergic reuptake inhibitor (NRIs)), and dual action antidepressants such as the serotonin noradrenaline reuptake inhibitors (SNRIs), the noradrenergic and dopaminergic reuptake inhibitor (NDRI) bupropion, and other compounds (e.g., mianserin, mirtazapine), which enhance the noradrenergic transmission". 
  92. ↑ "Clinical pharmacology of tomoxetine, a potential antidepressant". The Journal of Pharmacology and Experimental Therapeutics 232 (1): 139–143. January 1985. doi:10.1016/S0022-3565(25)20085-4. PMID 3965689. 
  93. ↑ 94.0 94.1 94.2 "Differential Potency of Venlafaxine, Paroxetine, and Atomoxetine to Inhibit Serotonin and Norepinephrine Reuptake in Patients With Major Depressive Disorder". Int J Neuropsychopharmacol 25 (4): 283–292. April 2022. doi:10.1093/ijnp/pyab086. PMID 34958348. 
  94. ↑ "Imaging the norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET: problems and progress". Nucl Med Biol 34 (6): 667–679. August 2007. doi:10.1016/j.nucmedbio.2007.03.013. PMID 17707807. 
  95. ↑ 96.0 96.1 "Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations". British Journal of Pharmacology 160 (2): 283–291. May 2010. doi:10.1111/j.1476-5381.2010.00707.x. PMID 20423340. 
  96. ↑ 97.0 97.1 "Inhibition of the NMDA and AMPA receptor channels by antidepressants and antipsychotics". Brain Research 1660: 58–66. April 2017. doi:10.1016/j.brainres.2017.01.028. PMID 28167075. 
  97. ↑ "Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors". Psychopharmacology 232 (12): 2191–2205. June 2015. doi:10.1007/s00213-014-3849-y. PMID 25572531. 
  98. ↑ "Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain--an in vivo study". Drug Design, Development and Therapy 7: 1433–1446. 2013. doi:10.2147/DDDT.S50448. PMID 24348020. 
  99. ↑ "Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study". Translational Psychiatry 4 (3): e373. March 2014. doi:10.1038/tp.2014.11. PMID 24643164. 
  100. ↑ "Attention deficit hyperactivity disorder and N-methyl-D-aspartate (NMDA) dysregulation". Current Pharmaceutical Design 20 (32): 5180–5185. 2014. doi:10.2174/1381612819666140110115227. PMID 24410567. 
  101. ↑ 102.0 102.1 102.2 "Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine". Neuropsychopharmacology 35 (7): 1560–1569. June 2010. doi:10.1038/npp.2010.27. PMID 20393461. 
  102. ↑ "Block of Voltage-Gated Sodium Channels by Atomoxetine in a State- and Use-dependent Manner". Front Pharmacol 12. 2021. doi:10.3389/fphar.2021.622489. PMID 33732157. 
  103. ↑ "Inhibitory effect of atomoxetine on Nav1.2 voltage-gated sodium channel currents". Pharmacol Rep 75 (3): 746–752. June 2023. doi:10.1007/s43440-023-00477-1. PMID 36914846. 
  104. ↑ "Atomoxetine increases salivary cortisol in healthy volunteers". J Psychopharmacol 21 (5): 545–549. July 2007. doi:10.1177/0269881106075274. PMID 17446206. 
  105. ↑ "The change of the cortisol levels in children with ADHD treated by methylphenidate or atomoxetine". J Psychiatr Res 46 (3): 415–416. March 2012. doi:10.1016/j.jpsychires.2011.11.014. PMID 22169529. 
  106. ↑ "Effects of stimulants and atomoxetine on cortisol levels in children with ADHD". Psychiatry Res 209 (3): 740–741. October 2013. doi:10.1016/j.psychres.2013.06.011. PMID 23850434. 
  107. ↑ 108.0 108.1 "Atomoxetine Drug Properties for Repurposing as a Candidate Alzheimer's Disease Therapeutic Agent". ACS Pharmacol Transl Sci 8 (11): 3757–3772. November 2025. doi:10.1021/acsptsci.5c00502. PMID 41262573. 
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  117. ↑ "Lilly loses ADD patent case, cuts revenue outlook". 12 August 2010. https://www.reuters.com/article/idUSN12148299/. 
  118. ↑ "Sun Pharma receives USFDA approval for generic Strattera capsules". International Business Times. http://www.ibtimes.com/articles/48022/20100901/sun-pharma-usfda-strattera-capsules-eli-lilly-atomoxetine-hydrochloride-attention-deficit-hyperactiv.htm. 
  119. ↑ "Sun Pharma Q1 2011-12 Earnings Call Transcript 10.00 am, July 29, 2011". http://www.sunpharma.com/images/finance/FY12%20Q1%20Earnings%20Call%20Transcript.pdf. 
  120. ↑ 121.0 121.1 "FDA approves first generic Strattera for the treatment of ADHD". U.S. Food and Drug Administration (FDA) (Press release). 30 May 2017. Archived from the original on 4 June 2017. Retrieved 1 January 2018.
  121. ↑ "Atomoxetine: a novel treatment for child and adult ADHD". Neuropsychiatric Disease and Treatment 2 (4): 455–466. December 2006. doi:10.2147/nedt.2006.2.4.455. PMID 19412494. 
  122. ↑ 123.0 123.1 123.2 "Eli Lilly and Company". 5 November 2023. https://adisinsight.springer.com/drugs/800000561. 
  123. ↑ "Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder". J Clin Psychiatry 64 Suppl 14: 6–17. 2003. PMID 14658930. 
  124. ↑ "Residual Fatigue in Unipolar and Bipolar Depression: A Systematic Review". Neuropsychopharmacol Rep 45 (1). March 2025. doi:10.1002/npr2.12519. PMID 39783764. 
  125. ↑ "Fatigue in Patients with Major Depressive Disorder: Prevalence, Burden and Pharmacological Approaches to Management". CNS Drugs 32 (1): 65–74. January 2018. doi:10.1007/s40263-018-0490-z. PMID 29383573. 
  126. ↑ "Comparative efficacy and safety of stimulant-type medications for depression: A systematic review and network meta-analysis". J Affect Disord 292: 416–423. September 2021. doi:10.1016/j.jad.2021.05.119. PMID 34144366. 
  127. ↑ "Adjunctive atomoxetine for residual fatigue in major depressive disorder". J Psychiatr Res 40 (4): 370–373. June 2006. doi:10.1016/j.jpsychires.2005.04.013. PMID 15978621. 
  128. ↑ "Addition of atomoxetine for depression incompletely responsive to sertraline: a randomized, double-blind, placebo-controlled study". J Clin Psychiatry 68 (4): 582–587. April 2007. doi:10.4088/jcp.v68n0414. PMID 17474814. 
  129. ↑ "Major Depression with ADHD: In Children and Adolescents". Psychiatry (Edgmont) 3 (4): 20–32. April 2006. PMID 21103168. 
  130. ↑ "Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms". J Am Acad Child Adolesc Psychiatry 44 (9): 915–924. September 2005. doi:10.1097/01.chi.0000169012.81536.38. PMID 16113620. 
  131. ↑ "Efficacy and safety of atomoxetine in adolescents with attention-deficit/hyperactivity disorder and major depression". J Child Adolesc Psychopharmacol 17 (4): 407–420. August 2007. doi:10.1089/cap.2007.0066. PMID 17822337. 
  132. ↑ "The noradrenergic paradox: implications in the management of depression and anxiety". Neuropsychiatr Dis Treat 12: 541–557. 2016. doi:10.2147/NDT.S91311. PMID 27042068. 
  133. ↑ "Pharmacotherapy for social anxiety disorder (SAnD)". Cochrane Database Syst Rev 10 (10). October 2017. doi:10.1002/14651858.CD001206.pub3. PMID 29048739. 
  134. ↑ "New frontiers in the pharmacological treatment of social anxiety disorder in adults: an up-to-date comprehensive overview". Expert Opin Pharmacother 24 (2): 207–219. February 2023. doi:10.1080/14656566.2022.2159373. PMID 36519357. 
  135. ↑ "Atomoxetine treatment in adults with attention-deficit/hyperactivity disorder and comorbid social anxiety disorder". Depress Anxiety 26 (3): 212–221. 2009. doi:10.1002/da.20549. PMID 19194995. 
  136. ↑ "A randomized controlled trial of atomoxetine in generalized social anxiety disorder". J Clin Psychopharmacol 29 (6): 561–564. December 2009. doi:10.1097/JCP.0b013e3181bf6303. PMID 19910721. 
  137. ↑ "A systematic review of the use of atomoxetine for management of comorbid anxiety disorders in children and adolescents with attention-deficit hyperactivity disorder". Res Dev Disabil 128. September 2022. doi:10.1016/j.ridd.2022.104275. PMID 35691145. 
  138. ↑ "The use of stimulants and atomoxetine in adults with comorbid ADHD and bipolar disorder". Expert Opinion on Pharmacotherapy 16 (14): 2193–2204. 2015. doi:10.1517/14656566.2015.1079620. PMID 26364896. 
  139. ↑ Autism Spectrum Disorder Parents Medication Guide. Washington, DC: American Academy of Child and Adolescent Psychiatry. 2016. p. 13. https://www.aacap.org/App_Themes/AACAP/Docs/resource_centers/autism/Autism_Spectrum_Disorder_Parents_Medication_Guide.pdf. "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" 
  140. ↑ "Anxiety reduction on atomoxetine and methylphenidate medication in children with ADHD". Pediatrics International 58 (6): 476–481. June 2016. doi:10.1111/ped.12847. PMID 26579704. 
  141. ↑ "Atomoxetine Efficacy in Methamphetamine Dependence during Methadone Maintenance Therapy". Archives of Iranian Medicine 22 (12): 692–698. December 2019. PMID 31823620. 
  142. ↑ 143.0 143.1 143.2 "Norepinephrine Reuptake Inhibition, an Emergent Treatment for Neurogenic Orthostatic Hypotension". Hypertension 81 (7): 1460–1466. July 2024. doi:10.1161/HYPERTENSIONAHA.124.22069. PMID 38766862. 
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  146. ↑ "Efficacy of atomoxetine versus midodrine for neurogenic orthostatic hypotension". Ann Clin Transl Neurol 7 (1): 112–120. January 2020. doi:10.1002/acn3.50968. PMID 31856425. 
  147. ↑ "Synergistic Pressor Effect of Atomoxetine and Pyridostigmine in Patients With Neurogenic Orthostatic Hypotension". Hypertension 73 (1): 235–241. January 2019. doi:10.1161/HYPERTENSIONAHA.118.11790. PMID 30571543. 
  148. ↑ "Atomoxetine augmentation of cholinesterase inhibitor therapy in patients with Alzheimer disease: 6-month, randomized, double-blind, placebo-controlled, parallel-trial study". Am J Geriatr Psychiatry 17 (9): 752–759. September 2009. doi:10.1097/JGP.0b013e3181aad585. PMID 19700948. 
  149. ↑ "A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment". Brain 145 (6): 1924–1938. June 2022. doi:10.1093/brain/awab452. PMID 34919634. 
  150. ↑ "Aroxybutynin/atomoxetine". 16 April 2026. https://adisinsight.springer.com/drugs/800060576. 
  151. ↑ "Aroxybutynin and atomoxetine (AD109) for the treatment of obstructive sleep apnea: Rationale, design and baseline characteristics of the phase 3 clinical trials". Contemp Clin Trials Commun 47. October 2025. doi:10.1016/j.conctc.2025.101538. PMID 41050845. 
  152. ↑ "The Combination of Aroxybutynin and Atomoxetine in the Treatment of Obstructive Sleep Apnea (MARIPOSA): A Randomized Controlled Trial". Am J Respir Crit Care Med 208 (12): 1316–1327. December 2023. doi:10.1164/rccm.202306-1036OC. PMID 37812772. 
  153. ↑ "Atomoxetine plus oxybutynin for obstructive sleep apnoea: a randomised-controlled trial with detailed pathophysiology". Thorax. April 2026. doi:10.1136/thorax-2025-224467. PMID 41932835. 
  154. ↑ "Atomoxetine/trazodone". 23 August 2022. https://adisinsight.springer.com/drugs/800061325. 
  155. ↑ "The effects of atomoxetine and trazodone combination on obstructive sleep apnea and sleep microstructure: A double-blind randomized clinical trial study". Sleep Med 113: 13–18. January 2024. doi:10.1016/j.sleep.2023.11.006. PMID 37979502. 
  156. ↑ "AD 113". 1 September 2023. https://adisinsight.springer.com/drugs/800063990. 
  157. ↑ "Atomoxetine and spironolactone combine to reduce obstructive sleep apnea severity and blood pressure in hypertensive patients". Sleep Breath 28 (6): 2571–2580. December 2024. doi:10.1007/s11325-024-03113-1. PMID 39305436. 
  158. ↑ "AD 182". 1 February 2023. https://adisinsight.springer.com/drugs/800061324. 
  159. ↑ "Effects of the Combination of Pimavanserin and Atomoxetine on OSA Severity: A Randomized Crossover Trial". Chest 168 (1): 223–235. July 2025. doi:10.1016/j.chest.2025.03.013. PMID 40158847. 
  160. ↑ "Acetazolamide Plus Atomoxetine for Obesity Hypoventilation Syndrome Treatment". Chest 169 (2): 527–537. February 2026. doi:10.1016/j.chest.2025.09.019. PMID 41015199. 
  161. ↑ "The combination of atomoxetine and dronabinol for the treatment of obstructive sleep apnea: a dose-escalating, open-label trial". J Clin Sleep Med 19 (7): 1183–1190. July 2023. doi:10.5664/jcsm.10528. PMID 36805833. 
  162. ↑ "Atomoxetine and fesoterodine combination improves obstructive sleep apnoea severity in patients with milder upper airway collapsibility". Respirology 27 (11): 975–982. November 2022. doi:10.1111/resp.14326. PMID 35811347. 
  163. ↑ "Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial". Respirology 26 (9): 878–886. September 2021. doi:10.1111/resp.14110. PMID 34164887. 
  164. ↑ "Atomoxetine for weight reduction in obese women: a preliminary randomised controlled trial". Int J Obes (Lond) 30 (7): 1138–1142. July 2006. doi:10.1038/sj.ijo.0803223. PMID 16418753. 
  165. ↑ "Placebo-controlled trial of atomoxetine for weight reduction in people with schizophrenia treated with clozapine or olanzapine". Clin Schizophr Relat Psychoses 5 (1): 17–25. April 2011. doi:10.3371/CSRP.5.1.3. PMID 21459735. 

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