Atomoxetine

Attention deficit hyperactivity disorder Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD). One of the primary differences with the standard stimulant treatments for ADHD is that it has no known misuse potential. 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. The benefits of atomoxetine against ADHD symptoms are dose-dependent until a plateau is reached. While its efficacy may be less than that of lisdexamfetamine, there is some evidence supporting its use in combination with stimulants. 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. Atomoxetine is thought to alleviate ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine levels in the prefrontal cortex, sharing 70–80% of the brain regions with stimulants in its produced effects. The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent. A further 2 to 4 weeks may be required for the full therapeutic effects to be seen. The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg. Other uses Cognitive disengagement syndrome Atomoxetine may be used to treat cognitive disengagement syndrome (CDS), Nocturnal enuresis Atomoxetine has been studied in the treatment of nocturnal enuresis in children and is effective for this indication. Excessive sleepiness Atomoxetine has wakefulness-promoting effects and is used off-label in the treatment of excessive sleepiness in for instance narcolepsy. 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). It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition, lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome. Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid hemorrhage in a case report. Available forms Atomoxetine is available in the form of oral capsules (10, 18, 25, 40, 60, 80, or 100mg) and in an oral solution (4mg/mL). It is taken once or twice daily. ==Contraindications==

Contraindications of atomoxetine include: • 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 or history thereof • Concomitant treatment with monoamine oxidase inhibitors (MAOIs) (and with at least 2weeks washout) • Narrow-angle glaucoma • Pregnancy and lactation • Hypersensitivity to atomoxetine or other constituents However, the FDA label states that in the case of cardiovascular disease, atomoxetine is only contraindicated in the case of severe cardiovascular disease. However, it states that atomoxetine should be used with caution in people with cardiovascular disease. 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. A precaution or relative contraindication is concomitant use of strong CYP2D6 inhibitors, which may necessitate atomoxetine dose adjustment. == Side effects ==

Common side effects include abdominal pain, decreased appetite, nausea, erectile dysfunction, feeling tired, dizziness, Atomoxetine has been found to modestly increase heart rate and blood pressure. 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. The drug can produce insomnia as a side effect, especially in CYP2D6 poor metabolizers, but has less overall risk of insomnia than methylphenidate or amphetamines. As of 2019, safety in pregnancy and breastfeeding is not clear; Serious side effects may include angioedema, liver problems, psychosis, heart problems, suicide, and aggression. nor the risk of sudden death. Rarely, atomoxetine can cause drug-induced liver injury or liver failure. The U.S. Food and Drug Administration (FDA) has issued a black box warning for suicidal behavior/ideation. Similar warnings have been issued in Australia. Unlike stimulant medications, atomoxetine does not have misuse liability or the potential to cause withdrawal effects upon abrupt discontinuation. Atomoxetine has been found to directly inhibit hERG potassium currents with an of 6,300nM, which has the potential to cause arrhythmia. No substantial QTc interval changes were observed in a clinical study of atomoxetine in CYP2D6 poor metabolizers. However, small changes could not be ruled out, and there was a slight but significant increase in QTc interval with higher atomoxetine concentrations. 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. ==Overdose==

Atomoxetine can lead to cardiac complications, with severe overdose requiring intensive medical care to avoid death. ==Interactions==

Atomoxetine is a substrate for CYP2D6. Drugs affecting gastric pH have no effect on the bioavailability or pharmacokinetics of atomoxetine. ==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. In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice. Atomoxetine is selective for the NET over many other targets. 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. 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. Conversely, venlafaxine robustly inhibited the SERT but only inhibited the NET at high doses. It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site. In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels. Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD. 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. Kir3.1/3.2 ion channels are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors. 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). The affinities () 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). Pharmacokinetics Absorption The absorption of atomoxetine with oral administration is rapid and complete. However, in CYP2D6 poor metabolizers, the half-life of atomoxetine is 19 to 21.6hours, or about 4-fold longer in comparison. In CYP2D6 extensive metabolizers, the half-lives of 4-hydroxyatomoxetine and N-desmethylatomoxetine are similar at around 6 to 8hours, whereas in CYP2D6 poor metabolizers, the half-life of N-desmethylatomoxetine is much longer at around 33 to 40hours. Atomoxetine levels in cerebrospinal fluid (CSF) with atomoxetine at a dosage of 80mg/day were 6.6ng/mL at 8hours post-dose and 1.4ng/mL at 24hours post-dose following 2weeks of administration. ==Chemistry==

Atomoxetine, or (−)-methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropylamine, is a white, granular powder that is highly soluble in water. File:Strattera 60mg capsule back.jpg|Strattera 60-mg capsule back File:Lilly Strattera 60mg Capsule.jpg|Strattera 60-mg capsule front with Lilly logo 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. ==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. 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. On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States. 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." In 2017 the FDA approved the generic production of atomoxetine by four pharmaceutical companies. ==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. 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. ==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. However, development for these indications was discontinued. It has also been studied and used to treat comorbid depression in people with ADHD. Atomoxetine has been studied in the treatment of social anxiety disorder, with mixed findings. The drug has been found to reduce anxiety symptoms in children and adolescents with ADHD and comorbid anxiety disorders. Atomoxetine may be used in those with ADHD and bipolar disorder although such use has not been well established. Some benefit has also been seen in people with ADHD and autism. 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 or methamphetamine dependence. Atomoxetine has been studied and used in the treatment of orthostatic hypotension. It has been reported to be more effective than midodrine. The drug synergistically increased blood pressure in combination with pyridostigmine. While acutely effective however, tachyphylaxis has been found to occur with continuous administration of atomoxetine. It has also been studied to treat mild cognitive impairment or prodromal Alzheimer's disease. Atomoxetine is being studied for treatment of sleep apnea in combination with various other drugs including oxybutynin or aroxybutynin, trazodone, antimineralocorticoids like spironolactone, an orexin receptor antagonist, pimavanserin, acetazolamide, dronabinol (Δ9-tetrahydrocannabinol; THC), fesoterodine, and zolpidem. Atomoxetine has been studied for reducing appetite and promoting weight loss in people with obesity, with mixed results. == References ==