Effects of Norepinephrine Reuptake Inhibition on Postural Tachycardia Syndrome
Open accessAbstract
Background: Postural tachycardia syndrome (POTS) is a disorder of chronic orthostatic intolerance accompanied by excessive orthostatic tachycardia. Patients with POTS commonly have comorbid conditions such as attention deficit hyperactivity disorder, depression, or fibromyalgia that are treated with medications that inhibit the norepinephrine reuptake transporter (NRI).NRI medications can increase sympathetic nervous system tone, which may increase heart rate (HR) and worsen symptoms in POTS patients. We sought to determine whether NRI with atomoxetine increases standing tachycardia or worsens the symptom burden in POTS patients. Methods and Results: Patients with POTS(n=27) underwent an acute drug trial of atomoxetine 40 mg and placebo on separate mornings in a randomized, crossover design. Blood pressure (BP),HR, and symptoms were assessed while seated and after standing prior to and hourly for 4 hours following study drug administration. Atomoxetine significantly increased standing HR compared with placebo (121±17 beats per minute versus 105±15 beats per minute;P=0.001) in POTS patients, with a trend toward higher standing systolic BP(P=0.072). Symptom scores worsened with atomoxetine compared to placebo (+4.2 au versus −3.5 au;P=0.028) from baseline to 2 hours after study drug administration. Conclusion: Norepinephrine reuptake inhibition with atomoxetine acutely increased standing HR and symptom burden in patients with POTS. Clinical Trials Registration: URL:http://clinicaltrials.gov. Unique identifier:NCT 00262470.
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The presence of another condition that could explain orthostatic tachycardia precludes the diagnosis of POTS.
“The presence of another condition that could explain the orthostatic tachycardia — such as anemia, anxiety, fever, pain, infection, dehydration, hyperthyroidism, pheochromocytoma, prolonged bed rest or the use of medications that can increase heart rate (including stimulants, diuretics and norepinephrine reuptake inhibitors)9 — precludes the diagnosis of POTS.”
From Diagnosis and management of postural orthostatic tachycardia syndrome (2022) · cites this paper as [9]
Methods > Subjects says participants had POTS symptoms in the absence of additional chronic disorders known to cause orthostatic intolerance. The Abstract > Methods and Results shows that the norepinephrine reuptake inhibitor atomoxetine increased standing heart rate in patients already diagnosed with POTS. The paper does not state that a medication or other condition capable of explaining orthostatic tachycardia precludes a POTS diagnosis. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPatients given Norepinephrine Reuptake Inhibition (NRI) atomoxetine reported increased symptom burden scores compared to placebo from baseline to 2 h after study drug administration.
“Patients given Norepinephrine Reuptake Inhibition (NRI) atomoxetine reported increased symptom burden scores compared to placebo from baseline to 2 h after study drug administration.”
From Self-reported symptom burden in postural orthostatic tachycardia syndrome (POTS): A narrative review of observational and interventional studies (2023) · cites this paper as Green et al., 2013
Treatments that improve symptoms of POTS might decrease the occurrence of syncope.
“Treatments that improve symptoms of POTS might decrease the occurrence of syncope, although this is unknown (24,514–523).”
From 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope (2017) · cites this paper as [519]
The Abstract’s Methods and Results and the Discussion > Symptoms section report changes in POTS symptom scores, but neither assesses whether symptom-improving treatments reduce syncope. A search for syncope and fainting found no passage in our copy addressing that proposed relationship. (LLM, conf=0.74)
Experimental — accuracy not yet measuredNET inhibitors or SNRIs can exacerbate tachycardia in POTS.
“Norepinephrine transporter (NET) inhibitors, or serotonin norepinephrine reuptake inhibitors (SNRIs), can exacerbate tachycardia in POTS [73].”
From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [73]
Iatrogenic inhibition of the norepinephrine transporter has been shown to engender a POTS-like state, increase upright heart rate, and exacerbate symptoms in POTS patients.
“Iatrogenic inhibition of the norepinephrine transporter has also been shown to engender a POTS-like state, increase upright heart rate, and exacerbate symptoms in POTS patients (46-49).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [46]
Administration of atomoxetine, a selective norepinephrine reuptake inhibitor, significantly increased the standing heart rate (from 105 bpm to 121 bpm) in POTS patients and resulted in greater symptoms of orthostatic intolerance.
“Administration of atomoxetine, a selective norepinephrine reuptake inhibitor (NRI), significantly increased the standing heart rate (from 105 bpm to 121 bpm) in POTS patients and resulted in greater symptoms of orthostatic intolerance (46).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [46]
A small randomized placebo-controlled study showed that the norepinephrine transporter inhibitor atomoxetine acutely worsens orthostatic tachycardia and symptoms in POTS.
“A small, randomized, placebo-controlled study showed that the NET inhibitor atomoxetine acutely worsens orthostatic tachycardia and symptoms in POTS”
From Postural tachycardia syndrome – Diagnosis, physiology, and prognosis (2018) · cites this paper as Green et al., 2013
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Go, S., Saito, N., Suzuki, S., Hatsushika, T., Kato, K., Kasuga, A., Kashiwagi, Y., & Kawashima, H. (2017) · Clinical Autonomic Research · doi:10.1007/s10286-017-0486-7 · Cited by 5 · see citing works
Verschure, D. O., Baas, F., van Eck‐Smit, B. L. F., Somsen, G. A., & Verberne, H. J. (2016) · Journal of Nuclear Cardiology · doi:10.1007/s12350-016-0722-x · Cited by 4 · see citing works
Psychological and Psychiatric Support; When, Why and What to Do
Opie, M., Raj, V., & Arnold, A. C. (2021) · Postural Tachycardia Syndrome · doi:10.1007/978-3-030-54165-1_40 · Cited by 3 · see citing works
Self-citationTidd, S. J. S., Nowacki, A. S., Singh, T. K., Hayburn, A., & Wilson, R. (2024) · General Hospital Psychiatry · doi:10.1016/j.genhosppsych.2024.01.003 · Cited by 2 · see citing works
Central Nervous System Stimulants and Drugs That Suppress Appetite
Bello, N. T. (2015) · Side effects of drugs annual · doi:10.1016/bs.seda.2015.08.004 · Cited by 2 · see citing works
Methylphenidate-Associated Syncope
Ferahkaya, H., & Uzun, N. (2022) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001567 · Cited by 2 · see citing works
Brown, C. R., & Foster, J. D. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.22.586171 · Cited by 2 · see citing works
Update on the Treatment of Autonomic Disorders
Eid, A. M., Vázquez-Vélez, G. E., Maliszewski, B., Butler, M., Bucelli, R. C., Perlmutter, J. S., & Luca, D. G. D. (2025) · Current Treatment Options in Neurology · doi:10.1007/s11940-025-00830-0 · Cited by 1 · see citing works
van Campen, C. M. C., & Visser, F. C. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14113648 · Cited by 2 · see citing works
Varma-Doyle, A. V., & Robbins, N. M. (2025) · Seminars in Neurology · doi:10.1055/a-2764-3644 · Cited by 1 · see citing works
Diagnostic et traitement du syndrome de tachycardie orthostatique posturale
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Hussein, M. T. E., & Hewko, A. (2024) · The Journal for Nurse Practitioners · doi:10.1016/j.nurpra.2024.105258 · Cited by 1 · see citing works
Differential Diagnosis of Vasovagal Syncope: Postural Orthostatic Tachycardia
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Self-citationOther Medications: Desmopressin, Pyridostigmine, Erythropoietin and SSRIs
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Central Nervous System Stimulants and Drugs That Suppress Appetite
Zahner, M. R., & Bello, N. T. (2016) · Side effects of drugs annual · doi:10.1016/bs.seda.2016.07.007
OBSOLETE: Sinus Tachycardias: Inappropriate Sinus Tachycardia and Postural Tachycardia Syndrome
Raj, S. R. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.99799-x
Self-citationCentral Nervous System Stimulants and Drugs That Suppress Appetite
Bello, N. T., & Zahner, M. R. (2017) · Side effects of drugs annual · doi:10.1016/bs.seda.2017.07.007
Clauss, N. J., & Daws, L. C. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00172-9
Sinus Tachycardias: Inappropriate Sinus Tachycardia and Postural Tachycardia Syndrome
Shaw, B. H., Ng, J., & Raj, S. R. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809657-4.99799-0
Self-citationSinus Tachycardias: Inappropriate Sinus Tachycardia and Postural Orthostatic Tachycardia Syndrome
Talati, A., Uppal, J., Sheldon, R. S., & Raj, S. R. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-15734-9.00016-9
Self-citationDziedzic, A., Furtak, D., Grela, W., Niewiadomska, J., Głogowska, P., Tulej, D., Marciniuk, D., Gniaź, N., Górska, A., & Marko, N. (2024) · Journal of Education Health and Sport · doi:10.12775/jehs.2024.71.56193
Sundarrajan, M., Ravichandran, V., & Ramachandran, R. (2024) · Biosciences Biotechnology Research Asia · doi:10.13005/bbra/3309
Postural Orthostatic Tachycardia Syndrome (POTS)
Chung, T., & Raj, S. R. (2026) · JAMA · doi:10.1001/jama.2026.14809
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Pocinki, A. G. (2026) · Heart Lung and Circulation · doi:10.1016/j.hlc.2026.04.118
- Authors
- Green, E. A., Raj, V., Shibao, C. A., Biaggioni, I., Black, B. K., Dupont, W. D., Robertson, D., & Raj, S. R.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Raj, Satish R.
- Venue
- Journal of the American Heart Association
- Published
- 2013-09-26
- Volume
- 2
- Issue
- 5
- Pages
- e000395-e000395
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC3835251
- OpenAlex
- W2123469787
- Cited by
- 64
- References
- 35
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 10 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 3 · 2017: 10 · 2016: 4 · 2015: 3 · 2014: 3
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- National Institutes of Health (UL1TR000445)
- National Heart, Lung, and Blood Institute (K23HL103976, P01HL056693, R01HL102387, P01 HL-56693)
- National Institute of Neurological Disorders and Stroke (U54NS065736)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Keywords
- postural orthostatic tachycardia syndrome, atomoxetine, norepinephrine reuptake inhibition, orthostatic intolerance, blood pressure, symptom burden, drug safety, comorbidities
- MeSH terms
- Atomoxetine Hydrochloride, Adult, Female, Heart Rate, Humans, Male, Propylamines, Severity of Illness Index, Cross-Over Studies, Adrenergic Uptake Inhibitors, Norepinephrine Plasma Membrane Transport Proteins, Postural Orthostatic Tachycardia Syndrome
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