Atomoxetine

• 1. Introduction

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  In 2023, atomoxetine was the 161st most commonly prescribed medication in the United States, with more than 3 million prescriptions. Most people know it by its brand name, Strattera. It treats attention deficit hyperactivity disorder, or ADHD, yet it behaves very differently from the drugs most people picture when they hear that diagnosis.

  What was the original plan for this medication, and why did that plan change? What does it actually do inside the brain? Why can the same dose produce such different results in two different bodies? And what else have doctors and researchers tried to treat with it?

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• 2. A Failed Antidepressant

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  Eli Lilly and Company, the drugmaker that filed the original patent, first hoped atomoxetine would become an antidepressant. Trials showed it was not effective enough against depression. It did work for ADHD, and the United States Food and Drug Administration approved it for that purpose in 2002. In the United States, Lilly manufactures, markets and sells it as the hydrochloride salt.

  The patent expired in May 2017, but the road to generic competition was uneven. On the 12th of August 2010, Lilly lost a lawsuit that challenged its patent. That raised the chance of an earlier generic entering the American market. On the 1st of September 2010, Sun Pharmaceuticals announced it would begin making a generic version in the United States.

  Then came a reversal. On a conference call on the 29th of July 2011, Sun's chairman said, "Lilly won that litigation on appeal so I think generic Strattera's deferred." Generic production finally arrived in 2017, when the FDA approved four pharmaceutical companies to make it.

  Tomoxetine was the drug's original name. It was changed to atomoxetine to avoid medication errors, because tomoxetine could be confused with tamoxifen.

  In India, brand names include Axetra, Axepta, Attera, Tomoxetin and Attentin. Poland uses Auroxetyn, Indonesia uses Xenocy, Iran uses Stramox, and Brazil uses Atentah. In Turkey it appears as Attex, Setinox and Atominex. France offers a quirk: the drug is not marketed there, yet hospitals dispense it under the Strattera name.

  Chemically, the compound is a white, granular powder that dissolves readily in water. What it does once it dissolves in the body begins with a single transporter protein.

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• 3. Targeting Norepinephrine

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  The norepinephrine transporter, abbreviated NET, is the main target of atomoxetine. This protein sits on the sending side of a synapse and pulls norepinephrine back into the nerve cell. Atomoxetine blocks it, so norepinephrine lingers across the brain. The drug also blocks dopamine reuptake in certain regions, such as the prefrontal cortex, where the dopamine transporter is scarce.

  Experiments in rats show how selective this is. Atomoxetine raised catecholamine levels in the prefrontal cortex without changing dopamine in the striatum or the nucleus accumbens. Methylphenidate, which blocks dopamine reuptake directly, raised dopamine in all three regions to the same degree. Mice showed a similar region-specific pattern. Even so, atomoxetine is thought to share 70-80% of the brain regions with stimulants in the effects it produces.

  Whether atomoxetine also blocks the serotonin transporter, or SERT, at clinical doses was long uncertain. A PET imaging study in rhesus monkeys found it occupied more than 90% of NET and more than 85% of SERT. Yet microdialysis studies in mice and rats found no rise in extracellular serotonin in the prefrontal cortex. In humans, platelet serotonin uptake was unaffected, while the pressor effects of tyramine, a marker of NET inhibition, were robustly blocked. Venlafaxine showed the opposite pattern, strongly inhibiting SERT but blocking NET only at high doses.

  Other targets turned up in laboratory work. In rat cortical neurons, atomoxetine acted as an NMDA receptor antagonist at therapeutic concentrations, with an IC50 of about 3,000 nM. Its binding site overlaps with the site used by magnesium ions. Abnormal glutamate and NMDA receptor function have been implicated in ADHD. The drug also reversibly inhibits GIRK potassium currents in Xenopus oocytes, and it inhibits voltage-gated sodium channels. Nobody knows whether the potassium effect contributes to its benefit in ADHD.

  The major active metabolite, 4-hydroxyatomoxetine, has its own profile. It acts as an antagonist at the mu-opioid receptor and a partial agonist at the kappa-opioid receptor, with IC50 values of 164 nM and 88 nM. Atomoxetine itself showed affinities 25- to 50-fold lower. It remains unknown whether these opioid actions cause any adverse effects in the central nervous system.

  One more human finding stands apart from the receptor tables: atomoxetine has been found to raise cortisol levels.

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• 4. Not a Stimulant

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  In rodents, amphetamine increases locomotor activity, but atomoxetine does not. Monkeys will self-administer amphetamine, but they do not self-administer atomoxetine. In humans, the drug produces no stimulant-like effects, no euphoria and no reinforcing effects. At the highest doses assessed, volunteers actually gave more negative and unpleasant ratings.

  The legal consequence is plain. Atomoxetine carries no risk of misuse and is not a controlled substance. Stopping it abruptly does not cause withdrawal effects. That sets it apart from the alpha-2 agonists guanfacine and clonidine, which cannot be stopped abruptly without significant withdrawal symptoms.

  In people given dextroamphetamine, atomoxetine reduced the stimulant, euphoriant and sympathomimetic effects. It also prevents the norepinephrine release that amphetamines cause.

  Doctors turn to non-stimulants like atomoxetine in several situations. A patient may have bothersome side effects from stimulants, or a stimulant may not have worked. Atomoxetine may be added to a stimulant to boost its effect. Cost can make stimulants impractical, and a history of substance use disorder can raise concern about misuse. Its efficacy may be lower than that of lisdexamfetamine, but some evidence supports combining it with stimulants.

  The clearest yardstick for how well it works is methylphenidate, a commonly prescribed stimulant.

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• 5. In the Clinic

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  Meta-analyses and systematic reviews comparing atomoxetine with methylphenidate found comparable efficacy and equal tolerability in children and adolescents. In adults, efficacy and tolerability are equivalent. The benefit against ADHD symptoms grows with dose until it reaches a plateau.

  The drug is approved for children, adolescents and adults, but it is recommended only for people at least six years old. Its efficacy has not been studied in younger children. Clinicians describe it as enhancing executive functions: self-motivation, sustained attention, inhibition, working memory, reaction time and emotional self-regulation. Like stimulants, it appears to reduce the emotional lability that accompanies ADHD in adults.

  Patience is part of the treatment. Initial therapeutic effects usually take 1 to 4 weeks to appear. A further 2 to 4 weeks may pass before the full effect is seen. The response can keep building for a year or longer.

  The maximum recommended total daily dose is 70 mg for children and adolescents and 100 mg for adults. Capsules come in strengths of 10, 18, 25, 40, 60, 80 and 100 mg, and an oral solution is made at 4 mg/mL. It is taken by mouth once or twice daily.

  Exposure rises in proportion to body weight, so doses must be adjusted by weight to produce equivalent exposure. But weight is not the biggest variable in how a body handles this drug.

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• 6. One Enzyme Decides

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  More than 90% of people are classed as extensive metabolizers, meaning an enzyme called CYP2D6 works at a normal level in their liver. Poor metabolizers, who have little of that activity, make up a small minority of up to 7%. For atomoxetine, that difference changes nearly every number.

  Absorption after swallowing is rapid and complete. Absolute bioavailability, the share of a dose that reaches the bloodstream, ranges from 63 to 94%. It is 63% in extensive metabolizers and 94% in poor metabolizers. Peak levels arrive after 1.0 hours in extensive metabolizers and 2.5 hours in poor ones. In poor metabolizers, peak levels are 5- to 6-fold higher and total exposure is 8- to 10-fold higher.

  Asian adults who carry two copies of the weakly active CYP2D6*10 variant fall in between. Their peak levels were about 1.5-fold higher and their total exposure 2-fold higher than in extensive metabolizers. Extensive metabolizers show little accumulation with repeated dosing, while poor metabolizers show significant accumulation.

  The half-life, the time for levels to fall by half, is 4.5 to 5.3 hours in extensive metabolizers. In poor metabolizers it stretches to 19 to 21.6 hours, about 4-fold longer. In studies with radiolabeled drug, radioactivity had a half-life of 62 hours in poor metabolizers versus 18 hours in extensive ones.

  Urine carries most of the drug away. Less than 3% leaves unchanged. In extensive metabolizers, more than 96% of a radiolabeled dose appears in urine within 24 hours. Poor metabolizers had excreted only 27% after 24 hours, and full excretion took about 144 hours.

  The major metabolite in every case is 4-hydroxyatomoxetine, which is made mainly by CYP2D6 and then attached to glucuronide for excretion. Another route, run by the enzyme CYP2C19, produces N-desmethylatomoxetine. Circulating 4-hydroxyatomoxetine is about 1% of atomoxetine levels in extensive metabolizers and about 0.1% in poor metabolizers.

  The bedside differences are measurable. Poor metabolizers had a greater heart rate increase, at +9.4-11 beats per minute versus +5.0-7.5. They also had a larger rise in blood pressure and more weight loss. Many side effects were about twice as frequent, and discontinuation rates were 11.2% versus 6.3%. The FDA label says dose adjustment may be necessary for poor metabolizers, while literature reviews say clinical trial experience does not require it.

  Drugs can imitate a poor metabolizer. Strong CYP2D6 inhibitors include bupropion, fluoxetine, paroxetine and quinidine. Bupropion raised atomoxetine exposure 5.1-fold. Paroxetine raised steady-state peak levels 3.5-fold, total exposure over 12 hours 6.5-fold, and the elimination half-life 2.5-fold. These inhibitors do not appear to change metabolism in people who are already poor metabolizers. In the other direction, atomoxetine has no clinically important effect on major cytochrome P450 enzymes. It raised exposure to midazolam by only 15%.

  Because the drug can be measured in plasma, serum or whole blood, a laboratory can tell extensive from poor metabolizers, confirm a suspected poisoning, or assist the forensic investigation of a fatal overdose.

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• 7. Risks and Warnings

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  Abdominal pain, decreased appetite, nausea, erectile dysfunction, tiredness, dizziness and urinary retention are the common side effects of atomoxetine. It modestly raises heart rate and blood pressure. A 2020 meta-analysis found associations with appetite suppression, weight loss and hypertension. It rated the drug a "potentially least preferred agent based on safety" for treating ADHD. Insomnia can occur, though the overall risk is lower than with methylphenidate or amphetamines.

  Angioedema, liver problems, psychosis, heart problems, suicide and aggression are listed among the serious side effects. The FDA has issued a black box warning for suicidal behavior and ideation, and Australia has issued similar warnings. Aggression and hostility may rise in children with ADHD, though such events are rare. Drug-induced liver injury and liver failure are also rare. In people with central autonomic failure, even very low doses can dramatically raise blood pressure.

  The heart is the subject of the most careful debate. Atomoxetine does not appear to raise the risk of stroke in adults or of sudden death. Yet the FDA label notes reports of sudden death, stroke and heart attack, which may be more likely with pre-existing cardiovascular disease. In the laboratory, the drug directly inhibits hERG potassium currents with an IC50 of 6,300 nM, which could in theory cause arrhythmia. A clinical study in poor metabolizers found no substantial QTc interval changes, but a slight, significant increase appeared at higher concentrations. QT prolongation has been reported at therapeutic doses and in overdose. A severe overdose can cause cardiac complications that require intensive care to prevent death.

  The list of contraindications is long. It includes moderate to severe hypertension, atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation, ventricular flutter, advanced arteriosclerosis and severe cardiovascular disorders. Uncontrolled hyperthyroidism, pheochromocytoma, narrow-angle glaucoma, pregnancy and lactation, and hypersensitivity to the drug are also on it. Monoamine oxidase inhibitors are excluded, with a washout of at least 2 weeks. The FDA label is narrower on the heart. It contraindicates the drug only in severe cardiovascular disease and advises caution otherwise, with extra thought for serious structural cardiac abnormalities.

  Pregnancy is unsettled. As of 2019, safety in pregnancy and breastfeeding is not clear. A 2018 review stated, "because of lack of data, the treating physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy." Animal studies found that the drug and its metabolites can cross the placenta, but fetal exposure was substantially lower than maternal exposure. Only a small amount reached milk in animals.

  Other medicines need care too. Because atomoxetine acts as an indirect sympathomimetic, it interacts with antihypertensives, pseudoephedrine, phenylephrine and other drugs that act on the adrenergic system. With highly protein-bound drugs, it could displace them from plasma proteins and strengthen their toxic effects. Concerns like these have not stopped researchers from testing the drug on conditions well outside ADHD.

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• 8. Beyond ADHD

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  Cognitive disengagement syndrome, or CDS, is the best-supported use outside ADHD. Multiple randomised controlled trials found atomoxetine effective for it, while multiple trials showed a poor response to methylphenidate. In children, atomoxetine has been studied for nocturnal enuresis and found effective. It promotes wakefulness, so doctors use it off-label for excessive sleepiness, for instance in narcolepsy.

  Traumatic brain injury produced a weaker result. A 2015 Cochrane review identified only one study of atomoxetine for it and found no positive effects. A case report did describe success in treating akinetic mutism that followed a subarachnoid hemorrhage.

  Eli Lilly formally developed the drug for major depressive disorder, Alzheimer's disease and Parkinson's disease. Development for those uses was discontinued, after the Parkinson's program had reached phase 3 clinical trials. Doctors still use atomoxetine off-label for depression, for example alongside SSRIs to treat leftover symptoms such as fatigue, although data are limited. It has also been used for depression that accompanies ADHD.

  Results in anxiety are mixed. Trials in social anxiety disorder gave mixed findings, but the drug reduced anxiety in children and adolescents who have ADHD and an anxiety disorder. Its use in people with ADHD and bipolar disorder is not well established. Some benefit has been seen in people with ADHD and autism. Research on mood symptoms has focused mainly on people with ADHD or methamphetamine dependence.

  Orthostatic hypotension, a drop in blood pressure on standing, is another target. Atomoxetine has been reported to be more effective than midodrine, and with pyridostigmine it synergistically raised blood pressure. The benefit fades, though. Tachyphylaxis, a loss of response, occurs with continuous administration, for reasons that are unclear.

  Sleep apnea is being studied with atomoxetine combined with other drugs. These include oxybutynin or aroxybutynin, trazodone, spironolactone, an orexin receptor antagonist, pimavanserin, acetazolamide, dronabinol, fesoterodine and zolpidem. Studies of appetite reduction and weight loss in people with obesity have produced mixed results.

  Alzheimer's disease development was discontinued, perhaps because of negative trial findings. Yet interest continued as of 2025, including studies in mild cognitive impairment and prodromal Alzheimer's disease. Researchers were still asking whether the drug could help patients at the earliest stage of memory decline.

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