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Atomoxetine

Atomoxetine, sold under the brand name Strattera,[7] is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD)[8] and, to a lesser extent, cognitive disengagement syndrome (CDS).[9][10][11] It may be used alone or along with psychostimulant medication.[12][13] It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time,[14] and emotional self-regulation.[15][16] Use of atomoxetine is only recommended for those who are at least six years old.[8] It is taken orally.[8] The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.

Common side effects of atomoxetine include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness.[8] Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression.[8][17] 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.[18]

It was approved for medical use in the United States in 2002.[8] In 2023, it was the 161st most commonly prescribed medication in the United States, with more than 3million prescriptions.[19][20]

Medical uses

Attention deficit hyperactivity disorder

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD). It is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old.[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.[23][24][25][26] The benefits of atomoxetine against ADHD symptoms are dose-dependent until a plateau is reached.[27]

While its efficacy may be less than that of lisdexamfetamine,[28] there is some evidence supporting its use in combination with stimulants.[12] 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;[29][30] 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.[31]

Atomoxetine is thought to alleviate ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine levels in the prefrontal cortex,[32] sharing 70–80% of the brain regions with stimulants in its produced effects.[33]

The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent.[5][34][35] A further 2 to 4 weeks may be required for the full therapeutic effects to be seen.[36][34] Incrementally increasing response may occur up to 1 year or longer.[35][37] The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg.[38]

Other uses

Cognitive disengagement syndrome

Atomoxetine may be used to treat cognitive disengagement syndrome (CDS),[10] as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment.[10][9][11] In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate.[39][40][41][42]

Nocturnal enuresis

Atomoxetine has been studied in the treatment of nocturnal enuresis in children and is effective for this indication.[43][44][45][46]

Excessive sleepiness

Atomoxetine has wakefulness-promoting effects and is used off-label in the treatment of excessive sleepiness in for instance narcolepsy.[47][48][49][50][51]

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).[52][53] It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition,[54] lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome.[52] A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects.[55] Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid hemorrhage in a case report.[53][56]

Cognitive disengagement syndrome

Atomoxetine may be used to treat cognitive disengagement syndrome (CDS),[10] as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment.[10][9][11] In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate.[39][40][41][42]

Nocturnal enuresis

Atomoxetine has been studied in the treatment of nocturnal enuresis in children and is effective for this indication.[43][44][45][46]

Excessive sleepiness

Atomoxetine has wakefulness-promoting effects and is used off-label in the treatment of excessive sleepiness in for instance narcolepsy.[47][48][49][50][51]

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).[52][53] It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition,[54] lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome.[52] A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects.[55] Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid hemorrhage in a case report.[53][56]

Available forms

Atomoxetine is available in the form of oral capsules (10, 18, 25, 40, 60, or 100mg) and in an oral solution (4mg/mL).[57][58] It is taken once or twice daily.

Contraindications

Contraindications include:[21][59]

  • 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
  • Pregnancy and lactation

Side effects

Common side effects include abdominal pain, decreased appetite, nausea, erectile dysfunction, feeling tired, dizziness,[8] and urinary retention.[60] Atomoxetine has been found to modestly increase heart rate and blood pressure.[61][62][63] 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.[64][65] The drug can produce insomnia as a side effect, especially in CYP2D6 poor metabolizers,[61][66][67] but has less overall risk of insomnia than methylphenidate or amphetamines.[66][68][69]

As of 2019, safety in pregnancy and breastfeeding is not clear;[18] a 2018 review stated that, "because of lack of data, the treating physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy."[70]

Serious side effects may include angioedema, liver problems, psychosis, heart problems, suicide, and aggression.[8][17] Atomoxetine does not appear to increase the risk of stroke in adults[71] nor the risk of sudden death.[63] The drug can dramatically increase blood pressure in people with central autonomic failure, even at very low doses.[72] Rarely, atomoxetine can cause drug-induced liver injury.[73]

Atomoxetine may increase the likelihood of aggression and hostility in children with ADHD, although such events are rare.[74] The U.S. Food and Drug Administration (FDA) has issued a black box warning for suicidal behavior/ideation.[6] Similar warnings have been issued in Australia.[21][75] Unlike stimulant medications, atomoxetine does not have misuse liability or the potential to cause withdrawal effects upon abrupt discontinuation.[21][22][76]

Atomoxetine has been found to directly inhibit hERG potassium currents with an IC50 of 6,300nM, which has the potential to cause arrhythmia.[77] No substantial QTc interval changes were observed in a clinical study of atomoxetine in CYP2D6 poor metabolizers.[78][79] However, small changes could not be ruled out, and there was a slight but significant increase in QTc interval with higher atomoxetine concentrations.[78][79] QT prolongation has been reported with atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used with other medications that may prolong the QT interval, concomitantly with CYP2D6 inhibitors, and caution to be used in poor metabolizers.

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

Overdose

Atomoxetine can lead to cardiac complications, with severe overdose requiring intensive medical care to avoid death.[80]

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.[81][82][83] The strong CYP2D6 inhibitor bupropion increased atomoxetine exposure by 5.1-fold and decreased 4-hydroxyatomoxetine-O-glucuronide exposure by 1.5-fold.[81]

Other notable drug interactions include:

Atomoxetine prevents norepinephrine release induced by amphetamines and has been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.[86][87][88]

  • 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[84][85]

Pharmacology

Pharmacodynamics

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.[84] 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.[91][92] In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.[93] Atomoxetine is selective for the NET over many other targets.[94][95]

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.[96] 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.[92][93] 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).[97] 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.[98][99] Conversely, venlafaxine robustly inhibited the SERT but only inhibited the NET at high doses.[98]

Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations (IC50 = ~3,000nM).[100][101] It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site.[100][101] 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.[102] In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels.[103] Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD.[104][105]

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.[106] Kir3.1/3.2 ion channels are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors.[106] Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers.[106] 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.[107][108]

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).[109] The affinities (IC50) of 4-hydroxyatomoxetine were 164nM for the MOR, 88nM for the KOR, 1,490nM for the δ-opioid receptor (DOR), and >5,000nM for the nociceptin receptor (ORL-1).[109] Atomoxetine itself showed dramatically lower affinities (e.g., 25- to 50-fold).[109] It is not known whether the actions of 4-hydroxyatomoxetine at the opioid receptors leads to CNS-related adverse effects with atomoxetine.[109]

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.[110][111][112]

Pharmacokinetics

Orally administered atomoxetine is rapidly and completely absorbed.[84] 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.[84] Maximum plasma concentration is reached in 1–2hours.[84] If taken with food, the maximum plasma concentration decreases by 10–40% and delays the tmax by 3hours.[84] Drugs affecting gastric pH have no effect on oral bioavailability.[38]

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.[84][113] It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%).[84][85] Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.[84]

The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19hours.[84][114] As atomoxetine is metabolized by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolizers.[114] Among CYP2D6 extensive metabolizers, the half-life of atomoxetine averaged 5.34hours and the half-life of the active metabolite N-desmethylatomoxetine was 8.9hours.[84][115] By contrast, among CYP2D6 poor metabolizers the half-life of atomoxetine averaged 20.0hours and the half-life of N-desmethylatomoxetine averaged 33.3hours.[84][115] Steady-state levels of atomoxetine are typically achieved at or around day 10 of regular dosing, with trough plasma concentrations (Ctrough) residing around 30–40ng/mL; however, both the time to steady-state levels and Ctrough are expected to vary based on a patient's CYP2D6 profile.[84][116]

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. 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.[38]

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.[84] 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.[84] CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.[84]

Pharmacogenomics

Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit 2-fold higher area-under-the-curve (AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolizers.[84]

Japanese men homozygous for CYP2D6*10 have similarly been found to experience 2-fold higher AUCs compared to extensive metabolizers.[84]

Pharmacogenomics

Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit 2-fold higher area-under-the-curve (AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolizers.[84]

Japanese men homozygous for CYP2D6*10 have similarly been found to experience 2-fold higher AUCs compared to extensive metabolizers.[84]

Chemistry

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

Synthesis

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.[119]

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.[120] 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.[121] On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.[122] 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."[123] In 2017 the FDA approved the generic production of atomoxetine by four pharmaceutical companies.[124]

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.[125]

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.[124]

Legal status

Atomoxetine has no risk of misuse and is not a controlled substance.[22][126]

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.[127] However, development for these indications was discontinued.[127] The drug reached phase 3 clinical trials for treatment of Parkinson's disease prior to being discontinued.[127] 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.[128][129][130][131][132][133] It has also been studied and used to treat comorbid depression in people with ADHD.[134][135][136]

Atomoxetine has been studied in the treatment of social anxiety disorder, with mixed findings.[137][138][139][140][141] The drug has been found to reduce anxiety symptoms in children and adolescents with ADHD and comorbid anxiety disorders.[142]

Atomoxetine may be used in those with ADHD and bipolar disorder although such use has not been well established.[143] Some benefit has also been seen in people with ADHD and autism.[144] 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[145] or methamphetamine dependence.[146]

Atomoxetine has been studied and used in the treatment of orthostatic hypotension.[147][148][149] It has been reported to be more effective than midodrine.[150][151] The drug synergistically increased blood pressure in combination with pyridostigmine.[152] While acutely effective however, tachyphylaxis has been found to occur with continuous administration of atomoxetine.[147][148] The reasons for this tolerance are unclear.[147]

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.[153][154] It has also been studied to treat mild cognitive impairment or prodromal Alzheimer's disease.[155]

Atomoxetine is being studied for treatment of sleep apnea in combination with various other drugs including oxybutynin or aroxybutynin,[156][157][158][159] trazodone,[160][161] antimineralocorticoids like spironolactone,[162][163] an orexin receptor antagonist.[164] pimavanserin,[165] acetazolamide,[166] dronabinol (Δ9-tetrahydrocannabinol; THC),[167] fesoterodine,[168] and zolpidem.[169]

Atomoxetine has been studied for reducing appetite and promoting weight loss in people with obesity, with mixed results.[170][171]

Further reading

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