Atomoxetine: Difference between revisions

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==Pharmacology==
==Pharmacology==
===Pharmacodynamics===
===Pharmacodynamics===
Atomoxetine inhibits [[Noradrenaline transporter|NET]], [[Serotonin transporter|SERT]], and [[Dopamine transporter|DAT]] with respective [[Dissociation constant|K<sub>i</sub>]] values of 5, 77, and 1451 nM.<ref name = PDSP /> In microdialysis studies, it increased [[Noradrenaline|NE]] and [[Dopamine|DA]] levels by three-fold in the [[prefrontal cortex]], but did not alter DA levels in the [[striatum]] or [[nucleus accumbens]].<ref name = NPP2002>{{cite journal|title=Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat: A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder|journal=Neuropsychopharmacology|date=November 2002|volume=27|issue=5|pages=699–711|doi=10.1016/S0893-133X(02)00346-9|pmid=12431845|author1=Bymaster, FP |author2=Katner, JS |author3=Nelson, DL |author4=Hemrick-Luecke, SK |author5=Threlkeld, PG |author6=Heiligenstein, JH |author7=Morin, SM |author8=Gehlert, DR |author9=Perry, KW |url=http://www.nature.com/npp/journal/v27/n5/pdf/1395936a.pdf|format=PDF}}</ref> Atomoxetine's selective increase in NE and DA are due to a lack of high concentrations of DAT in the prefrontal cortex (where the NET transports DA instead), and the nucleus accumbens's relative paucity of NE neurons.<ref>{{cite book|last1=Stahl|first1=Stephen M.|title=Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications|date=17 March 2008|publisher=Cambridge University Press|location=New York|isbn=9780521673761|page=891|edition=3rd|url=https://books.google.com/books?id=x6FqGPfe6AoC|accessdate=1 November 2015|ref=stahl2008|language=English|chapter=17|quote=Since the prefrontal cortex lacks high concentrations of DAT, DA is inactivated in this part of the brain by NET. Thus, inhibiting NET increases both DA and NE in the prefrontal cortex (Figures 12-36 and 17-21). However, since there are only a few NE neurons and NETs in nucleus accumbens, inhibiting NET does not lead to an increase in either NE or DA there (Figure 17-21). For this reason, in ADHD patients with deficient arousal and weak NE and DA signals in prefrontal cortex, a selective NRI such as atomoxetine increases both NE and DA in prefrontal cortex, enhancing tonic signaling of both, but it increases neither NE nor DA in the nucleus accumbens. Therefore atomoxetine has no abuse potential.}}</ref> A [[Positron emission tomography|PET imaging]] study of [[rhesus monkey]]s found that atomoxetine inhibited the NET and SERT with [[IC50|IC<sub>50</sub>]] values of 31&nbsp;ng/mL and 99&nbsp;ng/mL plasma, respectively, and that at clinically relevant doses, atomoxetine would occupy >90% of NET and >85% of SERT.<ref name="DingNaganawa2014">{{cite journal|last1=Ding|first1=Y.-S.|last2=Naganawa|first2=M.|last3=Gallezot|first3=J.-D.|last4=Nabulsi|first4=N.|last5=Lin|first5=S.-F.|last6=Ropchan|first6=J.|last7=Weinzimmer|first7=D.|last8=McCarthy|first8=T.J.|last9=Carson|first9=R.E.|last10=Huang|first10=Y.|last11=Laruelle|first11=M.|title=Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD|journal=NeuroImage|volume=86|year=2014|pages=164–171|issn=1053-8119|doi=10.1016/j.neuroimage.2013.08.001|pmid=23933039|quote=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}}</ref>
Atomoxetine inhibits the presynaptic [[norepinephrine transporter]], 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]] expression is minimal.<ref name = PMID15910008></ref> In rats, atomoxetine increased [[prefrontal cortex]] [[catecholamine]] concentrations without altering [[dopamine]] levels in the [[striatum]] or [[nucleus accumbens]]; in contrast, [[methylphenidate]] was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree.<ref name = NPP2002>{{cite journal|title=Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat: A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder|journal=Neuropsychopharmacology|date=November 2002|volume=27|issue=5|pages=699–711|doi=10.1016/S0893-133X(02)00346-9|pmid=12431845|author1=Bymaster, FP |author2=Katner, JS |author3=Nelson, DL |author4=Hemrick-Luecke, SK |author5=Threlkeld, PG |author6=Heiligenstein, JH |author7=Morin, SM |author8=Gehlert, DR |author9=Perry, KW |url=http://www.nature.com/npp/journal/v27/n5/pdf/1395936a.pdf|format=PDF}}</ref> In mice, atomoxetine was also found to increase prefrontal catecholamine levels without affecting striatal or accumbal levels.<ref name = PMID20403082>{{cite journal|last1=Koda|first1=K|last2=Ago|first2=Y|last3=Cong|first3=Y|last4=Kita|first4=Y|last5=Takuma|first5=K|last6=Matsuda|first6=T|title=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=Journal of neurochemistry|date=July 2010|volume=114|issue=1|pages=259-70|doi=10.1111/j.1471-4159.2010.06750.x|pmid=20403082}}</ref>


Atomoxetine's status as a [[Serotonin transporter|SERT]] inhibitor at clinical doses in humans is uncertain. A [[Positron emission tomography|PET imaging]] study on [[rhesus monkey]]s found that atomoxetine occupied >90% and >85% of neural norepinephrine and serotonin transporters, respectively.<ref name="DingNaganawa2014">{{cite journal|last1=Ding|first1=Y.-S.|last2=Naganawa|first2=M.|last3=Gallezot|first3=J.-D.|last4=Nabulsi|first4=N.|last5=Lin|first5=S.-F.|last6=Ropchan|first6=J.|last7=Weinzimmer|first7=D.|last8=McCarthy|first8=T.J.|last9=Carson|first9=R.E.|last10=Huang|first10=Y.|last11=Laruelle|first11=M.|title=Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD|journal=NeuroImage|volume=86|year=2014|pages=164–171|issn=1053-8119|doi=10.1016/j.neuroimage.2013.08.001|pmid=23933039|quote=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}}</ref> 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.<ref name = NPP2002></ref><ref name = PMID20403082></ref>
Atomoxetine also acts as an [[NMDA receptor antagonist]] at clinically relevant doses.<ref>{{cite journal|title=Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations|journal=British Journal of Pharmacology|date=May 2010|volume=160|issue=2|pages=283–291|pmid=20423340|doi=10.1111/j.1476-5381.2010.00707.x|pmc=2874851|author1=Ludolph, AG |author2=Udvardi, PT |author3=Schaz, U |author4=Henes, C |author5=Adolph, O |author6=Weigt, HU |author7=Fegert, JM |author8=Boeckers, TM |author9=Föhr, KJ |format=PDF}}</ref> The role of NMDA receptor antagonism in atomoxetine's therapeutic profile remains to be further elucidated, but recent literature has further implicated [[glutamatergic]] dysfunction as central in ADHD pathophysiology and etiology.<ref>{{cite journal|author1=Lesch, KP |author2=Merker, S |author3=Reif, A |author4=Novak, M |title=Dances with black widow spiders: dysregulation of glutamate signalling enters centre stage in ADHD|journal=European Neuropsychopharmacology |volume=23 |issue=6 |pages=479–491 |date=June 2013 |pmid=22939004|doi=10.1016/j.euroneuro.2012.07.013}}</ref><ref>{{cite web|url=http://www.eurekalert.org/pub_releases/2011-12/chop-ngs120111.php|title=New gene study of ADHD points to defects in brain signaling pathways|date=4 December 2011|work=Children's Hospital of Philadelphia}}</ref> [[4-Hydroxyatomoxetine]], the principle [[metabolite]] of atomoxetine, exhibits relatively weak affinity for [[Mu opioid receptor|μ-opioid receptors]] and [[κ-opioid receptor]]s. Creighton et al. reported antagonism of μ-opioid receptors and a [[partial agonist]] action at κ-opioid receptors.<ref name="pmid15225731">{{cite journal|last=Creighton|first=CJ|author2=Ramabadran, K|author3= Ciccone, PE|author4= Liu, J|author5= Orsini, MJ|author6= Reitz, AB|title=Synthesis and biological evaluation of the major metabolite of atomoxetine: elucidation of a partial kappa-opioid agonist effect.|journal=Bioorganic & Medicinal Chemistry Letters|date=2 August 2004|volume=14|issue=15|pages=4083–5|pmid=15225731|doi=10.1016/j.bmcl.2004.05.018}}</ref> The clinical significance of these effects are not known. Atomoxetine has been found to inhibit both brain and cardiac [[G protein-coupled inwardly-rectifying potassium channel]]s, a characteristic it shares with the related drug [[reboxetine]].<ref>{{cite journal|last=Kobayashi|first=T|author2=Washiyama, K |author3=Ikeda, K |title=Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine.|journal=Neuropsychopharmacology|date=Jun 2010|volume=35|issue=7|pages=1560–9|pmid=20393461|doi=10.1038/npp.2010.27|pmc=3055469}}</ref>


Atomoxetine has been found to act as an [[NMDA antagonist]] in rat cortical neurons, with an IC<sub>50</sub> of 3.47 µM.<ref name = PMID20423340>{{cite journal|title=Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations|journal=British Journal of Pharmacology|date=May 2010|volume=160|issue=2|pages=283–291|pmid=20423340|doi=10.1111/j.1476-5381.2010.00707.x|pmc=2874851|author1=Ludolph, AG |author2=Udvardi, PT |author3=Schaz, U |author4=Henes, C |author5=Adolph, O |author6=Weigt, HU |author7=Fegert, JM |author8=Boeckers, TM |author9=Föhr, KJ |format=PDF}}</ref><ref name = PMID28167075>{{cite journal|last1=Barygin|first1=OI|last2=Nagaeva|first2=EI|last3=Tikhonov|first3=DB|last4=Belinskaya|first4=DA|last5=Vanchakova|first5=NP|last6=Shestakova|first6=NN|title=Inhibition of the NMDA and AMPA receptor channels by antidepressants and antipsychotics.|journal=Brain research|date=1 April 2017|volume=1660|pages=58-66|doi=10.1016/j.brainres.2017.01.028|pmid=28167075}}</ref> It causes a use-dependent open-channel block and its binding site overlaps with the Mg<sup>2+</sup> binding site.<ref name = PMID20423340></ref><ref name = PMID28167075></ref> Atomoxetine's ability to increase prefrontal cortex firing rate in anesthetized rats could not be blocked by D<sub>1</sub> or α<sub>1</sub> receptor antagonists, but could be potentiated by [[NMDA]] or an α<sub>2</sub> receptor antagonist, suggesting a glutamatergic mechanism.<ref>{{cite journal|last1=Di Miceli|first1=M|last2=Gronier|first2=B|title=Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors.|journal=Psychopharmacology|date=June 2015|volume=232|issue=12|pages=2191-205|doi=10.1007/s00213-014-3849-y|pmid=25572531}}</ref> In [[Laboratory rat|Sprague Dawley rats]], atomoxetine reduces [[GRIN2B|NR2B]] protein content without altering transcript levels.<ref name = PMID24348020>{{cite journal|last1=Udvardi|first1=PT|last2=Föhr|first2=KJ|last3=Henes|first3=C|last4=Liebau|first4=S|last5=Dreyhaupt|first5=J|last6=Boeckers|first6=TM|last7=Ludolph|first7=AG|title=Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain--an in vivo study.|journal=Drug design, development and therapy|date=2013|volume=7|pages=1433-46|doi=10.2147/DDDT.S50448|pmid=24348020}}</ref> Aberrant glutamate and NMDA receptor function have been implicated in the etiology of [[ADHD]].<ref>{{cite journal|last1=Maltezos|first1=S|last2=Horder|first2=J|last3=Coghlan|first3=S|last4=Skirrow|first4=C|last5=O'Gorman|first5=R|last6=Lavender|first6=TJ|last7=Mendez|first7=MA|last8=Mehta|first8=M|last9=Daly|first9=E|last10=Xenitidis|first10=K|last11=Paliokosta|first11=E|last12=Spain|first12=D|last13=Pitts|first13=M|last14=Asherson|first14=P|last15=Lythgoe|first15=DJ|last16=Barker|first16=GJ|last17=Murphy|first17=DG|title=Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study.|journal=Translational psychiatry|date=18 March 2014|volume=4|pages=e373|doi=10.1038/tp.2014.11|pmid=24643164}}</ref><ref>{{cite journal|last1=Chang|first1=JP|last2=Lane|first2=HY|last3=Tsai|first3=GE|title=Attention deficit hyperactivity disorder and N-methyl-D-aspartate (NMDA) dysregulation.|journal=Current pharmaceutical design|date=2014|volume=20|issue=32|pages=5180-5|pmid=24410567}}</ref>
⚫
{| class="wikitable"

⚫
|+'''Binding profile'''<ref name=PDSP>{{cite web|title=PDSP K<sub>i</sub> Database |work=Psychoactive Drug Screening Program (PDSP) |author1=Roth, BL |author2=Driscol, J |url=http://pdsp.med.unc.edu/pdsp.php |publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health |accessdate=10 November 2013 |date=12 January 2011 |deadurl=yes |archiveurl=https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php |archivedate=8 November 2013 |df=dmy }}</ref><ref name = NPP2002 /><ref name="pmid15225731" /><ref>{{cite journal|last=Bymaster|first=FP|author2=Katner, JS|author3=Nelson, DL|author4=Hemrick-Luecke, SK|author5=Threlkeld, PG|author6=Heiligenstein, JH|author7=Morin, SM|author8=Gehlert, DR|author9= Perry, KW|title=Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder|journal=Neuropsychopharmacology|date=November 2002|volume=27|issue=5|pages=699–711|pmid=12431845|doi=10.1016/S0893-133X(02)00346-9}}</ref>
Atomoxetine also reversibly inhibits [[GIRK]] currents in [[Xenopus|''Xenopus'' oocytes]] in a concentration-dependent, voltage-independent, and time-independent manner. It inhibited K<sub>ir</sub>3.1/3.2, K<sub>ir</sub>3.2, and K<sub>ir</sub>3.1/3.4 currents, with IC<sub>50</sub>s of 10.9, 12.4, and 6.5 μM, respectively.<ref name = PMID20393461>{{cite journal|last1=Kobayashi|first1=T|last2=Washiyama|first2=K|last3=Ikeda|first3=K|title=Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine.|journal=Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology|date=June 2010|volume=35|issue=7|pages=1560-9|doi=10.1038/npp.2010.27|pmid=20393461}}</ref> K<sub>ir</sub>3.1/3.2 [[ion channel]]s are stimulated by [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]], [[Alpha-2 adrenergic receptor|α<sub>2</sub>]], [[Dopamine receptor D2|D<sub>2</sub>]], and [[Adenosine A1 receptor|A<sub>1</sub>]] stimulation and stimulation of other [[Gi alpha subunit|G<sub>i</sub>]]-coupled receptors.<ref name = PMID20393461></ref> Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers.<ref name = PMID20393461></ref> 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 receptor]]s, acting as an antagonist at [[Mu opioid receptor|μ-opioid receptors]] and a partial agonist at [[Kappa opioid receptor|κ-opioid receptors]].<ref name="PMID15225731">{{cite journal|last=Creighton|first=CJ|author2=Ramabadran, K|author3= Ciccone, PE|author4= Liu, J|author5= Orsini, MJ|author6= Reitz, AB|title=Synthesis and biological evaluation of the major metabolite of atomoxetine: elucidation of a partial kappa-opioid agonist effect.|journal=Bioorganic & Medicinal Chemistry Letters|date=2 August 2004|volume=14|issue=15|pages=4083–5|pmid=15225731|doi=10.1016/j.bmcl.2004.05.018}}</ref> It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.

⚫
{| class="wikitable sortable"
⚫
|+'''Binding profile of atomoxetine and its metabolites'''<ref name=PDSP>{{cite web|title=PDSP K<sub>i</sub> Database |work=Psychoactive Drug Screening Program (PDSP) |author1=Roth, BL |author2=Driscol, J |url=http://pdsp.med.unc.edu/pdsp.php |publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health |accessdate=10 November 2013 |date=12 January 2011 |deadurl=yes |archiveurl=https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php |archivedate=8 November 2013 |df=dmy }}</ref><ref name = NPP2002 /><ref name="pmid15225731" /><ref>{{cite journal|last=Bymaster|first=FP|author2=Katner, JS|author3=Nelson, DL|author4=Hemrick-Luecke, SK|author5=Threlkeld, PG|author6=Heiligenstein, JH|author7=Morin, SM|author8=Gehlert, DR|author9= Perry, KW|title=Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder|journal=Neuropsychopharmacology|date=November 2002|volume=27|issue=5|pages=699–711|pmid=12431845|doi=10.1016/S0893-133X(02)00346-9}}</ref><ref name = PMID15910008></ref>
|-
|-
! Protein !! K<sub>i</sub> (nM) for atomoxetine !! K<sub>i</sub> (nM) for 4-hydroxyatomoxetine !! K<sub>i</sub> (nM) for ''N''-desmethylatomoxetine
! Protein !! K<sub>i</sub> (nM) for atomoxetine !! K<sub>i</sub> (nM) for 4-hydroxyatomoxetine !! K<sub>i</sub> (nM) for ''N''-desmethylatomoxetine
|-
|-
| [[Serotonin transporter|SERT]] || 77 || ? || ?
| [[Serotonin transporter|SERT]] || 77 || ? || ?
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || >1000 || ? || ?
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || >1000 || ? || ?
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || >1000 || ? || ?
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || >1000 || ? || ?
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || >1000 || ? || ?
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || >1000 || ? || ?
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]] || >1000 || ? || ?
|-
|-
| [[Norepinephrine transporter|NET]] || 5 || ? || ?
| [[Norepinephrine transporter|NET]] || 5 || ? || ?
|-
|-
| [[Dopamine transporter|DAT]] || 1451 || ? || ?
| [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] || >1000 || ? || ?
|-
|-
| [[5-HT receptor]]s || >1000 || ? || ?
| [[Beta-1 adrenergic receptor|β<sub>1</sub>]] || >1000 || ? || ?
|-
|-
| [[Alpha adrenergic receptor]]s || >1000 || ? || ?
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] || >1000 || ? || ?
|-
|-
| [[Beta adrenergic receptor]]s || >1000 || ? || ?
| [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]] || >1000 || ? || ?
|-
|-
| [[Dopamine receptor|D<sub>1</sub> & D<sub>2</sub>]] || >1000 || ? || ?
| [[Dopamine transporter|DAT]] || 1451 || ? || ?
|-
|-
| [[Muscarinic acetylcholine receptor|M<sub>1</sub> & M<sub>2</sub>]] || >1000 || ? || ?
| [[Dopamine receptor D2|D<sub>2</sub>]] || >1000 || ? || ?
|-
|-
| [[Histamine receptor|H<sub>1</sub> & H<sub>2</sub>]] || >1000 || ? || ?
| [[Histamine receptor|H<sub>1</sub> & H<sub>2</sub>]] || >1000 || ? || ?
|-
|-
| [[Delta opioid receptor|δ<sub>1</sub> opioid receptor]] || ? || 300 || ?
| [[Delta opioid receptor|δOR]] || ? || 300 || ?
|-
|-
| [[Kappa opioid receptor|κ<sub>1</sub> opioid receptor]] || ? || 95 || ?
| [[Kappa opioid receptor|κOR]] || ? || 95 || ?
|-
|-
| [[Mu opioid receptor|μ opioid receptor]] || ? || 422 || ?
| [[Mu opioid receptor|μOR]] || ? || 422 || ?
|-
|-
| [[Sigma-1 receptor|σ<sub>1</sub> receptor]] || >1000 || ? || ?
| [[Sigma-1 receptor|σ<sub>1</sub>]] || >1000 || ? || ?
|}
|}
All values are for human receptors unless otherwise specified.


===Pharmacokinetics===
===Pharmacokinetics===

Revision as of 17:07, 6 August 2017

Atomoxetine
Clinical data
Trade namesStrattera
Other names(R)-N-Methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine
AHFS/Drugs.comMonograph
MedlinePlusa603013
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability63 to 94%[2][3][4]
Protein binding98%[2][3][4]
MetabolismHepatic, via CYP2D6[2][3][4]
Elimination half-life5.2 hours[2][3][4]
ExcretionRenal (80%) and faecal (17%)[2][3][4]
Identifiers
  • (3R)-N-Methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.120.306 Edit this at Wikidata
Chemical and physical data
FormulaC17H21NO
Molar mass255.36 g/mol
291.81 g/mol (hydrochloride) g·mol−1
3D model (JSmol)
  • CC1=C(C=CC=C1)O[C@H](CCNC)C2=CC=CC=C2
  • InChI=1S/C17H21NO/c1-14-8-6-7-11-16(14)19-17(12-13-18-2)15-9-4-3-5-10-15/h3-11,17-18H,12-13H2,1-2H3/t17-/m1/s1 checkY
  • Key:VHGCDTVCOLNTBX-QGZVFWFLSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Atomoxetine (brand name: Strattera) is a norepinephrine (noradrenaline) reuptake inhibitor which is approved for the treatment of attention deficit hyperactivity disorder (ADHD).[5] As of 2017 it is available as a generic medication in the United States.[6]

Medical uses

Attention deficit hyperactivity disorder

Atomoxetine is approved for use in children, adolescents, and adults.[5] However, its efficacy has not been studied in children under six years old.[3] Its primary advantage over the standard stimulant treatments for ADHD is that it has little known abuse potential.[3] 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 significant residual ADHD symptoms.[7]

The initial therapeutic effects of atomoxetine usually take 2–4 weeks to become apparent.[2] A further 2–4 weeks may be required for the full therapeutic effects to be seen.[8] Its efficacy may be less than that of stimulant medications.[9]

Unlike α2 adrenoceptor agonists such as guanfacine and clonidine, atomoxetine's use can be abruptly stopped without significant discontinuation effects being seen.[3]

Contraindications

Contraindications include:[3]

  • Hypersensitivity to atomoxetine or any of the excipients in the product
  • Symptomatic cardiovascular disease including:
-moderate to severe hypertension
-atrial fibrillation
-atrial flutter
-ventricular tachycardia
-ventricular fibrillation
-ventricular flutter
-advanced arteriosclerosis

Side effects

Incidence of adverse effects:[3][4][10][11]

Very common (>10% incidence) adverse effects include:

  • Nausea (26%)
  • Xerostomia (Dry mouth) (20%)
  • Appetite loss (16%)
  • Insomnia (15%)
  • Fatigue (10%)
  • Headache
  • Cough

Common (1-10% incidence) adverse effects include:

  • Constipation (8%)
  • Dizziness (8%)
  • Erectile dysfunction (8%)
  • Somnolence (sleepiness) (8%)
  • Abdominal pain (7%)
  • Urinary hesitation (6%)
  • Tachycardia (high heart rate) (5-10%)
  • Hypertension (high blood pressure) (5-10%)
  • Irritability (5%)
  • Abnormal dreams (4%)
  • Dyspepsia (4%)
  • Ejaculation disorder (4%)
  • Hyperhidrosis (abnormally increased sweating) (4%)
  • Vomiting (4%)
  • Hot flashes (3%)
  • Paraesthesia (sensation of tingling, tickling, etc.) (3%)
  • Menstrual disorder (3%)
  • Weight loss (2%)
  • Depression
  • Sinus headache
  • Dermatitis
  • Mood swings

Uncommon (0.1-1% incidence) adverse effects include:

Rare (0.01-0.1% incidence) adverse effects including

The FDA of the US has issued a black box warning for suicidal behaviour/ideation.[4] Similar warnings have been issued in Australia.[3][13] Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.[3]

Overdose

Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500 mg of atomoxetine have not resulted in death.[3] The most common symptoms of overdose include:[3]

  • Gastrointestinal symptoms
  • Somnolence
  • Dizziness
  • Tremor
  • Abnormal behaviour
  • Hyperactivity
  • Agitation
  • Dry mouth
  • Tachycardia
  • Hypertension
  • Mydriasis

Less common symptoms:[3]

The recommended treatment for atomoxetine overdose includes use of activated charcoal to prevent further absorption of the drug.[3]

Pharmacology

Pharmacodynamics

Atomoxetine inhibits the presynaptic norepinephrine transporter, 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 expression is minimal.[14] In rats, atomoxetine increased prefrontal cortex catecholamine concentrations without altering dopamine levels in the striatum or nucleus accumbens; in contrast, methylphenidate was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree.[15] In mice, atomoxetine was also found to increase prefrontal catecholamine levels without affecting striatal or accumbal levels.[16]

Atomoxetine's status as a 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 norepinephrine and serotonin transporters, respectively.[17] 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.[15][16]

Atomoxetine has been found to act as an NMDA antagonist in rat cortical neurons, with an IC50 of 3.47 µM.[18][19] It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site.[18][19] Atomoxetine's ability to increase prefrontal cortex firing rate in anesthetized rats could not be blocked by D1 or α1 receptor antagonists, but could be potentiated by NMDA or an α2 receptor antagonist, suggesting a glutamatergic mechanism.[20] In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels.[21] Aberrant glutamate and NMDA receptor function have been implicated in the etiology of ADHD.[22][23]

Atomoxetine also reversibly inhibits GIRK currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner. It inhibited Kir3.1/3.2, Kir3.2, and Kir3.1/3.4 currents, with IC50s of 10.9, 12.4, and 6.5 μM, respectively.[24] Kir3.1/3.2 ion channels are stimulated by M2, α2, D2, and A1 stimulation and stimulation of other Gi-coupled receptors.[24] Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolizers.[24] 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.[25] It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.

Binding profile of atomoxetine and its metabolites[26][15][27][28][14]
Protein Ki (nM) for atomoxetine Ki (nM) for 4-hydroxyatomoxetine Ki (nM) for N-desmethylatomoxetine
SERT 77 ? ?
5-HT1A >1000 ? ?
5-HT1B >1000 ? ?
5-HT1D >1000 ? ?
5-HT2A >1000 ? ?
5-HT2C >1000 ? ?
5-HT6 >1000 ? ?
5-HT7 >1000 ? ?
NET 5 ? ?
α2A >1000 ? ?
β1 >1000 ? ?
M1 >1000 ? ?
M2 >1000 ? ?
DAT 1451 ? ?
D2 >1000 ? ?
H1 & H2 >1000 ? ?
δOR ? 300 ?
κOR ? 95 ?
μOR ? 422 ?
σ1 >1000 ? ?

All values are for human receptors unless otherwise specified.

Pharmacokinetics

Orally administered atomoxetine is rapidly and completely absorbed.[14] Hepatic first-pass metabolism is dependent on CYP2D6 activity, resulting in an absolute bioavailability of 63% for extensive metabolizers and 94% for poor metabolizers.[14] Maximum plasma concentration is reached in 1-2 hours.[14] If taken with food, the maximum plasma concentration decreases by 10-40% and delays the tmax by 1 hour.[14]

Atomoxetine has a volume of distribution of 0.85 L/kg, with limited partitioning into red blood cells.[14] It is highly bound to plasma proteins (98.7%), mainly albumin.[14] Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.[14]

The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours.[14][29] As atomoxetine is metabolized by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolizers.[29]

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.[14]

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.[14] The fractions excreted as 4-hydroxyatomoxetine and its glucuronide are 86% of a given dose in extensive metabolizers, but only 40% in poor metabolizers.[14] CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.[14]

Major metabolites of atomoxetine in humans.[14]

Pharmacogenomics

Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higher AUCs and 1.5-fold higher maximum plasma concentrations compared to extensive metabolizers.[14]

Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolizers.[14]

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.[30][31][32]

CYP2D6 is not very susceptible to enzyme induction.[33] Other possible drug interactions include:[3]

Chemistry and composition

Atomoxetine is designated chemically as (−)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, and has a molecular mass of 291.82.[5] It has a solubility of 27.8 mg/ml in water.[5] Atomoxetine is a white solid that exists as a granular powder inside the capsule, along with pregelatinized starch and dimethicone.[5] The capsule shells contain gelatin, sodium lauryl sulfate, FD&C Blue No. 2, yellow iron oxide, titanium dioxide, red iron oxide, edible black ink, and trace amounts of other inactive ingredients.[5]

  • 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

Detection in biological fluids

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.[34]

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. It is under patent until 2017.[35] On May 30, 2017 the FDA approved the generic production by four pharmaceutical companies.[36] 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.[37] On 1 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.[38] 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."[39]

Brand names

In India, atomoxetine is sold under brand names including Attentrol [Sun Pharma], Axepta, [Intas Pharma] Attera [Icon pharma], Tomoxetin [Torrent Pharma], Atokem [Alkem Pharma], and Attentin [Ranbaxy Pharma].

In Romania, atomoxetine is sold under the brand name Strattera.

In Iran, atomoxetine is sold under brand names including stramox by TeKaJe Co.

Research

There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, particularly in cases with concomitant ADHD.[40][41][42]

See also

  • Orphenadrine (modified base and similar termination of the molecule) it is a variant of the same structure
  • Fluoxetine (modified base and same termination of the molecule)

References

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ a b c d e f "atomoxetine (Rx) – Strattera". Medscape Reference. WebMD. Retrieved 10 November 2013.
  3. ^ a b c d e f g h i j k l m n o p q "STRATTERA® (atomoxetine hydrochloride)". TGA eBusiness Services. Eli Lilly Australia Pty. Limited. 21 August 2013. Retrieved 10 November 2013.
  4. ^ a b c d e f g "ATOMOXETINE HYDROCHLORIDE capsule [Mylan Pharmaceuticals Inc.]". DailyMed. Mylan Pharmaceuticals Inc. October 2011. Retrieved 10 November 2013.
  5. ^ a b c d e f "STRATTERA® (atomoxetine hydrochloride) CAPSULES for Oral Use. Full Prescribing Information" (PDF). Indianapolis, USA: Eli Lilly and Company. 20 February 2014. Retrieved 23 May 2014.
  6. ^ "Press Announcements - FDA approves first generic Strattera for the treatment of ADHD". www.fda.gov. Retrieved 2 June 2017.
  7. ^ Ghuman, Jaswinder K.; Hutchison, Shari L. (1 November 2014). "Atomoxetine is a second-line medication treatment option for ADHD". Evidence Based Mental Health. 17 (4): 108–108. doi:10.1136/eb-2014-101805. ISSN 1468-960X. PMID 25165169.
  8. ^ Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
  9. ^ Kooij, JJS (2013). Adult ADHD Diagnostic Assessment and Treatment (PDF). Springer London. doi:10.1007/978-1-4471-4138-9. ISBN 978-1-4471-4137-2.
  10. ^ "Strattera 10mg, 18mg, 25mg, 40mg, 60mg, 80mg or 100mg hard capsules". electronic Medicines Compendium. 28 May 2013. Retrieved 10 November 2013.
  11. ^ "Strattera Product Insert". Retrieved 8 December 2013.
  12. ^ "STRATTERA Medication Guide" (PDF). Eli Lilly and Company. 2003. Retrieved 17 December 2013.
  13. ^ "Atomoxetine and suicidality in children and adolescents". Australian Prescriber. Vol. 36, no. 5. October 2013. p. 166. Archived from the original on 10 November 2013. Retrieved 10 November 2013. {{cite news}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  14. ^ a b c d e f g h i j k l m n o p q Sauer, JM; Ring, BJ; Witcher, JW (2005). "Clinical pharmacokinetics of atomoxetine". Clinical pharmacokinetics. 44 (6): 571–90. doi:10.2165/00003088-200544060-00002. PMID 15910008.
  15. ^ a b c Bymaster, 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" (PDF). Neuropsychopharmacology. 27 (5): 699–711. doi:10.1016/S0893-133X(02)00346-9. PMID 12431845.
  16. ^ a b Koda, 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. PMID 20403082.
  17. ^ Ding, Y.-S.; Naganawa, M.; Gallezot, J.-D.; Nabulsi, N.; Lin, S.-F.; Ropchan, J.; Weinzimmer, D.; McCarthy, T.J.; Carson, R.E.; Huang, Y.; Laruelle, M. (2014). "Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD". NeuroImage. 86: 164–171. doi:10.1016/j.neuroimage.2013.08.001. ISSN 1053-8119. 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
  18. ^ a b Ludolph, AG; Udvardi, PT; Schaz, U; Henes, C; Adolph, O; Weigt, HU; Fegert, JM; Boeckers, TM; Föhr, KJ (May 2010). "Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations" (PDF). British Journal of Pharmacology. 160 (2): 283–291. doi:10.1111/j.1476-5381.2010.00707.x. PMC 2874851. PMID 20423340.
  19. ^ a b Barygin, OI; Nagaeva, EI; Tikhonov, DB; Belinskaya, DA; Vanchakova, NP; Shestakova, NN (1 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. PMID 28167075.
  20. ^ 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. PMID 25572531.
  21. ^ Udvardi, PT; Föhr, KJ; Henes, C; Liebau, S; Dreyhaupt, J; Boeckers, TM; Ludolph, AG (2013). "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: 1433–46. doi:10.2147/DDDT.S50448. PMID 24348020.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ Maltezos, S; Horder, J; Coghlan, S; Skirrow, C; O'Gorman, R; Lavender, TJ; Mendez, MA; Mehta, M; Daly, E; Xenitidis, K; Paliokosta, E; Spain, D; Pitts, M; Asherson, P; Lythgoe, DJ; Barker, GJ; Murphy, DG (18 March 2014). "Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study". Translational psychiatry. 4: e373. doi:10.1038/tp.2014.11. PMID 24643164.
  23. ^ Chang, JP; Lane, HY; Tsai, GE (2014). "Attention deficit hyperactivity disorder and N-methyl-D-aspartate (NMDA) dysregulation". Current pharmaceutical design. 20 (32): 5180–5. PMID 24410567.
  24. ^ a b c Kobayashi, T; Washiyama, K; Ikeda, K (June 2010). "Inhibition of G-protein-activated inwardly rectifying K+ channels by the selective norepinephrine reuptake inhibitors atomoxetine and reboxetine". Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 35 (7): 1560–9. doi:10.1038/npp.2010.27. PMID 20393461.
  25. ^ Creighton, CJ; Ramabadran, K; Ciccone, PE; Liu, J; Orsini, MJ; Reitz, AB (2 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. PMID 15225731.
  26. ^ Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 November 2013. Retrieved 10 November 2013. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  27. ^ Cite error: The named reference pmid15225731 was invoked but never defined (see the help page).
  28. ^ Bymaster, 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. PMID 12431845.
  29. ^ a b Brown, JT; Bishop, JR (2015). "Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability". Pharmacogenomics. 16 (13): 1513–20. doi:10.2217/PGS.15.93. PMID 26314574.
  30. ^ Todor, I; Popa, A; Neag, M; Muntean, D; Bocsan, C; Buzoianu, A; Vlase, L; Gheldiu, AM; Briciu, C (NaN). "Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers". Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques. 19 (2): 198–207. PMID 27518170. {{cite journal}}: Check date values in: |date= (help)
  31. ^ Kasi, PM; Mounzer, R; Gleeson, GH (2011). "Cardiovascular side effects of atomoxetine and its interactions with inhibitors of the cytochrome p450 system". Case reports in medicine. 2011: 952584. doi:10.1155/2011/952584. PMID 21765848.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  32. ^ Belle, DJ; Ernest, CS; Sauer, JM; Smith, BP; Thomasson, HR; Witcher, JW (November 2002). "Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics". Journal of clinical pharmacology. 42 (11): 1219–27. PMID 12412820.
  33. ^ Horn, John R.; Hansten, Philip D. (2008). "Get to Know an Enzyme: CYP2D6". Pharmacy Times. Retrieved 19 February 2015.
  34. ^ Baselt, Randall C. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 118–20. ISBN 0-931890-08-X.
  35. ^ "Patent and Exclusivity Search Results". Electronic Orange Book. US Food and Drug Administration. Retrieved 26 April 2009.
  36. ^ [FDA.org/news events/newsroom/press announcements/ucm561096.htm FDA.org/news events/newsroom/press announcements/ucm561096.htm]. {{cite web}}: Check |url= value (help); Cite has empty unknown parameter: |dead-url= (help); Missing or empty |title= (help)
  37. ^ "Drugmaker Eli Lilly loses patent case over ADHD drug, lowers revenue outlook". Chicago Tribune.
  38. ^ "Sun Pharma receives USFDA approval for generic Strattera capsules". International Business Times. Archived from the original on 7 April 2011. {{cite news}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  39. ^ "Sun Pharma Q1 2011-12 Earnings Call Transcript 10.00 am, July 29, 2011" (PDF). Archived from the original (PDF) on 29 September 2011. {{cite news}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  40. ^ 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. PMID 16649828. {{cite journal}}: Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help)
  41. ^ Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH (October 2005). "Augmentation with open-label atomoxetine for partial or non-response to antidepressants". The Journal of Clinical Psychiatry. 66 (10): 1234–8. doi:10.4088/JCP.v66n1005. PMID 16259536.
  42. ^ 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. PMID 16113620. {{cite journal}}: Unknown parameter |lastauthoramp= ignored (|name-list-style= suggested) (help)

External links

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