Atomoxetine

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.04.2021
Released 11.13.2003
Expires For CME 09.04.2024

Atomoxetine

Author: K K Jain MD†

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Atomoxetine

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Introduction

Historical note and terminology

Most of the drugs for the treatment of attention-deficit/hyperactivity disorder (ADHD) have been CNS stimulants in the past. Originally called tomoxetine, the drug's name was changed to atomoxetine to avoid any potential confusion with the anticancer drug tamoxifen that might lead to dispensing errors. Atomoxetine is not a controlled substance in the United States. It is the first nonstimulant approved by the FDA for the treatment of ADHD in children, adolescents, and adults.

Pharmacology

Atomoxetine is a selective norepinephrine reuptake inhibitor. The molecular formula is C17H21NO•HCl.

Atomoxetine (chemical structure)

(Contributed by Dr. K K Jain.)

Pharmacodynamics. The exact mechanism by which atomoxetine produces its therapeutic effects in ADHD is unknown, but it is likely by selective inhibition of the presynaptic norepinephrine transporter, as determined by ex vivo uptake and neurotransmitter depletion studies. It has little or no affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors.

In experimental studies, atomoxetine has been shown to block N-methyl-d-aspartate receptors, which may be relevant to its clinical effects in the treatment of ADHD, as altered glutamatergic transmission might play a role in ADHD (17).

Use of stop-signal functional MRI on healthy volunteers has shown that atomoxetine exerts its beneficial effects on inhibitory control in ADHD via modulation of right inferior frontal function (06). Atomoxetine is associated with increased fMRI activation of dorsolateral prefrontal cortex, parietal cortex, and cerebellum, but not dorsal anterior midcingulate cortex (03). A randomized clinical trial using functional near-infrared spectroscopy to monitor the oxy-hemoglobin signal changes of ADHD in children has shown that activation in the right inferior and middle prefrontal gyri could serve as an objective neurofunctional biomarker to indicate the effects of atomoxetine on inhibitory control in ADHD (18). Although these effects are like those of methylphenidate, they are not identical.

Pharmacokinetics. The pharmacokinetics of atomoxetine patients has been well characterized over a wide range of doses and is similar in pediatric patients and adult subjects after adjustment for body weight. Important features are:

	• Atomoxetine is well absorbed after oral administration.
	• Maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing.
	• Atomoxetine has a half-life of about 5 hours.
	• The duration of action for atomoxetine can be up to 24 hours, depending on its rate of metabolism.
	• At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin.
	• It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 enzymatic pathway and subsequent glucuronidation.
	• Atomoxetine is excreted, mainly in the urine, and less than 3% of the dose is excreted as unchanged atomoxetine, indicating extensive biotransformation.

Pharmacogenetics. Genetic polymorphisms of CYP2C19 have a significant effect on the pharmacokinetics of atomoxetine (08). Plasma levels of atomoxetine are markedly raised in subjects with mutations of the CYP2D6 gene, increasing the risk of concentration-related adverse events of atomoxetine (04). Atomoxetine needs to be adjusted for individuals who are CYP2D6 poor metabolizers, individuals who are taking a strong CYP2D6 inhibitor (eg, paroxetine, fluoxetine, and quinidine), and individuals with moderate or severe hepatic impairment. However, various regulatory authorities have different dosing recommendations. For CYP2D6 poor metabolizers, the Clinical Pharmacogenetics Implementation Consortium recommends that if no clinical response is observed after 2 weeks of atomoxetine therapy, then a plasma concentration exposure check be used with an individual’s CYP2D6 genotype to help clinicians guide dose selection and titration (02).

Indications

Atomoxetine is indicated for the treatment of ADHD.

Off-label uses

	• Atomoxetine has been used as an adjunct in the management of fibromyalgia syndrome.
	• Tourette syndrome.
	• Adult patients with treatment-resistant depression.
	• As adjunct to conventional antidepressants for residual fatigue in major depressive disorders.
	• For improving cognition in patients with schizophrenia.
	• Atomoxetine monotherapy for improving symptoms of ADHD and comorbid social anxiety disorder in adults.
	• Encopresis or fecal soiling in children with ADHD (14).
	• An open-label study showed that atomoxetine did not benefit children with severe autistic disorder who have ADHD symptoms (07).
	• In an open study, atomoxetine improved cognitive and behavioral deficits in Parkinson disease, which supports the hypothesis that targeting dopaminergic insensitive noradrenergic dysfunction is a useful strategy (16).
	• Atomoxetine has a synergistic effect on motor cortex excitability and motor learning in healthy humans by enhancing norepinephrine transmission (22).
	• Elderly patients with primary orthostatic hypotension (13).
	• Atomoxetine, combined with intensive speech therapy, has been shown to be safe and feasible for patients with post-stroke aphasia (29).
	• A systematic review of literature has shown that treatment with atomoxetine of patients with Parkinson disease resulted in improvements in executive dysfunction, including impulsivity, risk taking, and global cognition (27). Long-term larger clinical trials are required to define the therapeutic potential of atomoxetine for executive dysfunction in Parkinson disease.
	• A study with functional ultrasound, which enables the imaging of brain activity through the regional monitoring of cerebral blood volume (CBV) dynamics, has shown that atomoxetine consistently increases cerebral blood volume in the visual cortex, the dentate gyrus, and thalamus in a dose-dependent manner in the anesthesized rat (26). This method can be standardized to improve our understanding of the mechanism of action of drugs in development on the brain.

Goals and duration of treatment

Atomoxetine is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome. Long-term efficacy, safety, and tolerability of atomoxetine for the treatment of adult ADHD has been shown in several studies. Whereas many adults with ADHD respond relatively rapidly to atomoxetine, others respond more gradually without a clear plateau at 24 weeks, indicating that longer duration of treatment may increase the number of responders (24). In a retrospective study, children who were prescribed a stimulant medication in addition to atomoxetine had better outcomes in ADHD than those receiving only atomoxetine (21). A comprehensive metaanalysis of studies of parent-rated outcomes has shown that atomoxetine produces significant improvement in core symptom of ADHD and is a viable option for treatment (12).

Predictors of relapse or maintenance of response have been identified in patients with ADHD following discontinuation of long-term treatment with atomoxetine in clinical trials. In pediatric patients, less maintenance of response was associated with prerandomization presence of ADHD Rating Scale-IV-Parent Version Investigator-Rated item “does not listen;” in adults, less maintenance of response was associated with prerandomization presence of Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator-Rated:Screening Version (CAARS-Inv:SV) items “loses things” and “difficulty awaiting turn” (25). An EEG study has shown that patients with decreased theta cordance values, especially in the left temporoparietal region, at 1 week were likely to respond to atomoxetine whereas those without any such change were likely to be nonresponders (23).

Adverse effects

The most common side effects of atomoxetine are headache, abdominal pain, loss of appetite, nausea, vomiting, and vertigo. These effects are usually temporary and do not require reduction of dose. Use of atomoxetine has been associated with persistent camptocormia, which is characterized by forward flexion of the spine when standing or walking (01).

Atomoxetine has significantly less abuse liability than methylphenidate or phentermine and no greater abuse liability than desipramine. Patients with ADHD can be safely switched from neurostimulants, specifically methylphenidate, to atomoxetine and may benefit from symptom improvement. There is no evidence of symptom rebound or adverse events suggesting a drug-discontinuation or withdrawal syndrome. Children with ADHD may be at risk for seizures but use of atomoxetine does not appear to elevate this risk further. A black-box warning for suicidal ideation has been published in the United States prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Atomoxetine has been reported to induce bruxism that improves by treatment with buspirone (30). An adult with ADHD developed a delusional state during treatment with atomoxetine, which resolved after discontinuation of the drug and antipsychotic (15). A middle-aged man with acute intracerebral hemorrhage in the right pons and midbrain, who was treated with atomoxetine once daily to improve cognitive impairment, suddenly developed episodes of uncontrollable and inappropriate laughter, which resolved after discontinuation of the drug (19). Rarely, atomoxetine may cause complex partial seizures with transient hypoperfusion of the temporal, parietal, and occipital lobes shown on MRI as well as focal slowing and spikes and sharp waves in EEG, which resolve on discontinuation of the drug (11).

Other adverse events include reversible drug-induced liver injury and hypertension in patients with impaired autonomic function. For a detailed listing of the adverse events, see the Physicians’ Desk Reference.

References

01: Bhattacharya A, Praharaj SK, Sinha VK. Persistent camptocormia associated with atomoxetine in a child with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2014;24(10):596-7. PMID 25469421
02: Brown JT, Bishop JR, Sangkuhl K, et al. Clinical pharmacogenetics implementation consortium guideline for cytochrome P450 (CYP)2D6 genotype and atomoxetine therapy. Clin Pharmacol Ther 2019;106(1):94-102.** PMID 30801677
03: Bush G, Holmes J, Shin LM, et al. Atomoxetine increases fronto-parietal functional MRI activation in attention-deficit/hyperactivity disorder: a pilot study. Psychiatry Res 2013;211(1):88-91. PMID 23146254
04: Byeon JY, Kim YH, Na HS, et al. Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites. Arch Pharm Res 2015;38(11):2083-91. PMID 26254792
05: Camporeale A, Porsdal V, De Bruyckere K, et al. Safety and tolerability of atomoxetine in treatment of attention deficit hyperactivity disorder in adult patients: an integrated analysis of 15 clinical trials. J Psychopharmacol 2015;29(1):3-14. PMID 25424623
06: Chamberlain SR, Hampshire A, Müller U, et al. Atomoxetine modulates right inferior frontal activation during inhibitory control: a pharmacological functional magnetic resonance imaging study. Biol Psychiatry 2009;65(7):550-5. PMID 19026407
07: Charnsil C. Efficacy of atomoxetine in children with severe autistic disorders and symptoms of ADHD: an open-label study. J Atten Disord 2011;15(8):684-9. PMID 20686100
08: Choi CI, Bae JW, Lee YJ, Lee HI, Jang CG, Lee SY. Effects of CYP2C19 genetic polymorphisms on atomoxetine pharmacokinetics. J Clin Psychopharmacol 2014;34(1):139-42. PMID 24346747
09: Cunill R, Castells X, Tobias A, Capella D. Atomoxetine for attention deficit hyperactivity disorder in the adulthood: a meta-analysis and meta-regression. Pharmacoepidemiol Drug Saf 2013;22(9):961-9. PMID 23813665
10: Durell TM, Adler LA, Williams DW, et al. Atomoxetine treatment of attention-deficit/hyperactivity disorder in young adults with assessment of functional outcomes: a randomized, double-blind, placebo-controlled clinical trial. J Clin Psychopharmacol 2013;33(1):45-54. PMID 23277268
11: Finsterer J, Scorza FA. Atomoxetine-induced focal seizures with contralateral hypoperfusion and hyper-CKemia. Radiol Case Rep 2020;16(2):369-71.** PMID 34168713
12: Gayleard JL, Mychailyszyn MP. Atomoxetine treatment for children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD): a comprehensive meta-analysis of outcomes on parent-rated core symptomatology. Atten Defic Hyperact Disord 2017;9(3):149-60. PMID 28110366
13: Hale GM, Brenner M. Atomoxetine for orthostatic hypotension in an elderly patient over 10 weeks: a case report. Pharmacotherapy 2015;35(9):e141-8. PMID 26406777
14: Hergüner S, Hergüner A. Atomoxetine for encopresis in 2 children with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol 2012;32(2):302-3. PMID 22388168
15: Howes CF, Sharp C. Delusional infestation in the treatment of ADHD with atomoxetine. BMJ Case Rep 2018;2018. PMID 30249731
16: Kehagia AA, Housden CR, Regenthal R, et al. Targeting impulsivity in Parkinson's disease using atomoxetine. Brain 2014;137(Pt 7):1986-97. PMID 24893708
17: Ludolph AG, Udvardi PT, Schaz U, et al. Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations. Br J Pharmacol 2010;160(2):283-91. PMID 20423340
18: Nagashima M, Monden Y, Dan I, et al. Neuropharmacological effect of atomoxetine on attention network in children with attention deficit hyperactivity disorder during oddball paradigms as assessed using functional near-infrared spectroscopy. Neurophotonics 2014;1(2):025007. PMID 26157979
19: Park JM, Kim YW, Choi S. Atomoxetine (Strattera)-induced pathologic laughing in a patient with pontine hemorrhage: a case report. Clin Neuropharmacol 2021;44(2):77-9.** PMID 33480614
20: Ravishankar V, Chowdappa SV, Benegal V, Muralidharan K. The efficacy of atomoxetine in treating adult attention deficit hyperactivity disorder (ADHD): A meta-analysis of controlled trials. Asian J Psychiatr 2016;24:53-8. PMID 27931908
21: Scott NG, Ripperger-Suhler J, Rajab MH, Kjar D. Factors associated with atomoxetine efficacy for treatment of attention-deficit/hyperactivity disorder in children and adolescents. J Child Adolesc Psychopharmacol 2010;20(3):197-203. PMID 20578932
22: Sczesny-Kaiser M, Bauknecht A, Hoffken O, et al. Synergistic effects of noradrenergic modulation with atomoxetine and 10 Hz repetitive transcranial magnetic stimulation on motor learning in healthy humans. BMC Neurosci 2014;15:46. PMID 24690416
23: Singh G, Arun P, Das S, Kaur D. Can EEG predict response to atomoxetine in attention deficit hyperactivity disorder at 1 week? J Atten Disord 2021;25(5):758-67.** PMID 30762472
24: Sobanski E, Leppämäki S, Bushe C, Berggren L, Casillas M, Deberdt W. Patterns of long-term and short-term responses in adult patients with attention-deficit/hyperactivity disorder in a completer cohort of 12 weeks or more with atomoxetine. Eur Psychiatry 2015;30(8):1011-20. PMID 26512449
25: Thome J, Dittmann RW, Greenhill LL, et al. Predictors of relapse or maintenance of response in pediatric and adult patients with attention-deficit/hyperactivity disorder following discontinuation of long-term treatment with atomoxetine. Atten Defic Hyperact Disord 2017;9(4):219-29. PMID 28477289
26: Vidal B, Droguerre M, Venet L, et al. Functional ultrasound imaging to study brain dynamics: application of pharmaco-fUS to atomoxetine. Neuropharmacology 2020;179:108273. PMID 32801025
27: Warner CB, Ottman AA, Brown JN. The role of atomoxetine for Parkinson disease-related executive dysfunction: a systematic review. J Clin Psychopharmacol 2018;38(6):627-31.** PMID 30346335
28: Wehmeier PM, Schacht A, Escobar R, Hervas A, Dickson R. Health-related quality of life in ADHD: a pooled analysis of gender differences in five atomoxetine trials. Atten Defic Hyperact Disord 2012;4(1):25-35. PMID 22271466
29: Yamada N, Kakuda W, Yamamoto K, Momosaki R, Abo M. Atomoxetine administration combined with intensive speech therapy for post-stroke aphasia: evaluation by a novel SPECT method. Int J Neurosci 2016;126(9):829-38. PMID 26335615
30: Yuce M, Karabekiroglu K, Say GN, Mujdeci M, Oran M. Buspirone use in the treatment of atomoxetine-induced bruxism. J Child Adolesc Psychopharmacol 2013;23(9):634-5. PMID 24206098

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Atomoxetine

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Atomoxetine Hydrochloride

Atomoxetine

Atomoxetine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

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to access the full version.

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Also in This Category

Wilson disease

Anti-LGI1 encephalitis

Drug-induced myasthenic syndromes

Hypothyroidism

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Familial Alzheimer disease

Acupuncture

Hyperventilation syndrome

	• Atomoxetine is contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product.
	• Atomoxetine should not be taken with a MAO inhibitor or within 2 weeks after discontinuing MAO inhibitor.
	• Atomoxetine increases the risk of mydriasis; therefore, its use is not recommended in patients with narrow angle glaucoma.

Atomoxetine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Wilson disease

Anti-LGI1 encephalitis

Drug-induced myasthenic syndromes

Hypothyroidism

Fatal familial insomnia

Familial Alzheimer disease

Acupuncture

Hyperventilation syndrome

This is an article preview.
Start a Free Account
to access the full version.