Atomoxetine, sold under the brand name Strattera among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD). It may be used alone or along with stimulants. Use is only recommended in those who are at least six years old. It is taken by mouth.
Atomoxetine was approved for medical use in the United States in 2002. A month's supply in the United Kingdom costs the NHS about £53 as of 2019. In the United States, the wholesale cost of this amount is about 77 USD. In 2016, it was the 245th most prescribed medication in the United States, with more than 2 million prescriptions.
Atomoxetine is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. Its primary advantage over the standard stimulant treatments for ADHD is that it has little known abuse potential. While it has been shown to significantly reduce inattentive and hyperactive symptoms, the responses were lower than the response to stimulants. Additionally, 40% of participants who were treated with atomoxetine experienced residual ADHD symptoms.
The initial therapeutic effects of atomoxetine usually take 2–4 weeks to become apparent. A further 2–4 weeks may be required for the full therapeutic effects to be seen. Its efficacy may be less than that of stimulant medications.
The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg.
Doctors may prescribe non-stimulants including atomoxetine when a person has bothersome side effects from stimulants; when a stimulant was not effective; or in combination with a stimulant to increase effectiveness.
Atomoxetine may be used in those with ADHD and bipolar disorder although such use has not been well studied. Some benefit has also been seen in people with ADHD and autism.
The FDA of the US has issued a black box warning for suicidal behaviour/ideation. Similar warnings have been issued in Australia. Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.
The recommended treatment for atomoxetine overdose includes use of activated charcoal to prevent further absorption of the drug.
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.
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
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All values are for human receptors unless otherwise specified. arat cortex. bXenopus oocytes. Additional sources:
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. Supporting atomoxetine's selectivity, a human study found no effects on platelet serotonin uptake (a marker of SERT inhibition) and inhibition of the pressor effects of tyramine (a marker of NET inhibition).
Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations. It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site. Atomoxetine's ability to increase prefrontal cortex firing rate in anesthetized rats could not be blocked by D1 or α2-adrenergic receptor antagonists, but could be potentiated by NMDA or an α1-adrenergic receptor antagonist, suggesting a glutaminergic mechanism. 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 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. Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers. It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.
4-Hydroxyatomoxetine, the major active metabolite of atomoxetine in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity for opioid receptors, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors. It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.
Orally administered atomoxetine is rapidly and completely absorbed. 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. Maximum plasma concentration is reached in 1–2 hours. If taken with food, the maximum plasma concentration decreases by 10-40% and delays the tmax by 1 hour. Drugs affecting gastric pH have no effect on oral bioavailability.
Atomoxetine has a volume of distribution of 0.85 L/kg, with limited partitioning into red blood cells. It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%). Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.
The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours. As atomoxetine is metabolized by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolizers.
Atomoxetine, N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhbition of CYP1A2 and CYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6-17 μmol/L. Plasma concentrations of 4-hydroxyatomoxetine and N-desmethylatomoxetine at steady state are 1.0% and 5% that of atomoxetine in CYP2D6 extensive metabolizers, and are 5% and 45% that of atomoxetine in CYP2D6 poor metabolizers.
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. 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. CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.
Atomoxetine may be quantitated in plasma, serum or whole blood in order 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.
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 May 30, 2017 the FDA approved the generic production by four pharmaceutical companies. 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."
Society and culture
In India, atomoxetine is sold under brand names including AXETRA, Axepta, Attera, Tomoxetin, and Attentin. In Australia and Romania, atomoxetine is sold under the brand name Strattera. In Iran, atomoxetine is sold under brand names including Stramox. In 2017, a generic version was approved in the United States.
There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, particularly in cases with concomitant ADHD.
^"Parent's Medication Guide: ADHD". American Psychiatric Association (Guidelines (Tertiary source)). American Psychiatric Association & American Academy of Child and Adolescent Psychiatry (AACAP). June 2013. Archived from the original on 2 February 2017. Retrieved 1 January 2017. Though not FDA-approved for combined treatment, atomoxetine (Strattera) is sometimes used in conjunction with stimulants as an off-label combination therapy.
^ abcBritish national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 344–345. ISBN9780857113382.
^Matthew Siegel, MD., Craig Erickson, MD., MS, Jean A. Frazier, MD., Toni Ferguson, Autism Society of America., Eric Goepfert, MD., Gagan Joshi, MD., Quentin Humberd, MD., Bryan H. King, MD., Amy Lutz, EASI Foundation: Ending Aggression and Self-Injury in the Developmentally Disabled., Louis Kraus, MD., Alice Mao, MD., Adelaide Robb, MD., Jeremy Veenstra-VanderWeele, MD, PhD., Paul Wang, MD, Autism SpeaksCarmen J. Head, MPH, CHES, Director, Research, Development, & WorkforceEve, Bender, Scientific Editor. (2016). Autism_Spectrum_Disorder_Parents_Medication_Guide(PDF). 3615 Wisconsin Avenue, NW, Washington, DC 20016-3007: American Academy of Child and Adolescent Psychiatry. p. 13. Archived(PDF) from the original on 11 April 2017. 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.CS1 maint: multiple names: authors list (link) CS1 maint: extra text: authors list (link)
^Todor I, Popa A, Neag M, Muntean D, Bocsan C, Buzoianu A, Vlase L, Gheldiu AM, Briciu C (April–June 2016). "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. doi:10.18433/j3h03r. PMID27518170.
^Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
^ abcdBymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (November 2002). "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. doi:10.1016/S0893-133X(02)00346-9. PMID12431845.
^ abCreighton CJ, Ramabadran K, Ciccone PE, Liu J, Orsini MJ, Reitz AB (August 2004). "Synthesis and biological evaluation of the major metabolite of atomoxetine: elucidation of a partial kappa-opioid agonist effect". Bioorganic & Medicinal Chemistry Letters. 14 (15): 4083–5. doi:10.1016/j.bmcl.2004.05.018. PMID15225731.
^ abKoda K, Ago Y, Cong Y, Kita Y, Takuma K, Matsuda T (July 2010). "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): 259–70. doi:10.1111/j.1471-4159.2010.06750.x. PMID20403082.
^Ding YS, Naganawa M, Gallezot JD, Nabulsi N, Lin SF, Ropchan J, Weinzimmer D, McCarthy TJ, Carson RE, Huang Y, Laruelle M (February 2014). "Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD". NeuroImage. 86: 164–71. doi:10.1016/j.neuroimage.2013.08.001. PMID23933039. 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
^Zerbe RL, Rowe H, Enas GG, Wong D, Farid N, Lemberger L (January 1985). "Clinical pharmacology of tomoxetine, a potential antidepressant". The Journal of Pharmacology and Experimental Therapeutics. 232 (1): 139–43. PMID3965689.
^ abBarygin OI, Nagaeva EI, Tikhonov DB, Belinskaya DA, Vanchakova NP, Shestakova NN (April 2017). "Inhibition of the NMDA and AMPA receptor channels by antidepressants and antipsychotics". Brain Research. 1660: 58–66. doi:10.1016/j.brainres.2017.01.028. PMID28167075.
^Di Miceli M, Gronier B (June 2015). "Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors". Psychopharmacology. 232 (12): 2191–205. doi:10.1007/s00213-014-3849-y. PMID25572531.
^Spencer TJ, Faraone SV, Michelson D, Adler LA, Reimherr FW, Glatt SJ & Biederman J (March 2006). "Atomoxetine and adult attention-deficit/hyperactivity disorder: the effects of comorbidity". The Journal of Clinical Psychiatry. 67 (3): 415–20. doi:10.4088/JCP.v67n0312. PMID16649828.
^Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH (October 2005). "Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants". The Journal of Clinical Psychiatry. 66 (10): 1234–8. doi:10.4088/JCP.v66n1005. PMID16259536.
^Kratochvil CJ, Newcorn JH, Arnold LE, Duesenberg D, Emslie GJ, Quintana H, Sarkis EH, Wagner KD, Gao H, Michelson D & Biederman J (September 2005). "Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms". Journal of the American Academy of Child and Adolescent Psychiatry. 44 (9): 915–24. doi:10.1097/01.chi.0000169012.81536.38. PMID16113620.