Received: 12 July 2022 | Accepted: 6 August 2022

DOI: 10.1002/pcn5.41

CASE REPORT

Serotonin syndrome induced by overdose of atomoxetine

alone in a patient with attention‐deficit hyperactivity disorder:
A case report

Fumika Sato MD | Akihito Suzuki MD, PhD | Keisuke Noto MD, PhD |
Toshinori Shirata MD, PhD | Muneaki Kanno MD, PhD |
Ryota Kobayashi MD, PhD | Koichi Otani MD, PhD

Department of Psychiatry, Yamagata Abstract

University School of Medicine, Yamagata,
Japan
Correspondence
Toshinori Shirata, MD, PhD, Department of
Psychiatry, Yamagata University School of
Medicine, 2‐2‐2 Iida‐Nishi, Yamagata 990‐
9585, Japan.
Email: toshirata@med.id.yamagata-u.ac.jp
Background: Serotonin syndrome is characterized by mental status changes,
autonomic hyperactivity, and neuromuscular abnormalities. This syndrome results
from various medications that engender serotonergic overactivity. Atomoxetine is a
norepinephrine reuptake inhibitor used for the treatment of attention‐deficit
hyperactivity disorder (ADHD). Two case reports have described serotonin
syndrome induced by the combination of atomoxetine with venlafaxine or
methylphenidate, but no report describes this syndrome induced by atomoxetine
alone. This report describes serotonin syndrome induced solely by an overdose of
atomoxetine in a patient with ADHD.
Case Presentation: The patient in this case was a 21‐year‐old man who had been
treated with atomoxetine for ADHD. He was transported to our hospital 1 h after
intentional ingestion of 1200 mg of atomoxetine in a suicide attempt. On admission, he
showed profuse diaphoresis, marked agitation, somnolence, slight fever, tachycardia,
prolonged QT interval, myoclonus, tremor, and hyperreflexia. He was diagnosed as
having serotonin syndrome and was treated with administration of activated charcoal
and massive infusion. Three days later, his serotonin syndrome symptoms had
disappeared completely.
Conclusion: Findings in this case suggest that atomoxetine alone can cause
serotonin syndrome presumably via its effects of serotonin reuptake inhibition.
Clinicians should consider this syndrome induced by atomoxetine overdose.

KEYWORDS
attention‐deficit hyperactivity disorder (ADHD), atomoxetine, overdose, serotonin syndrome

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© 2022 The Authors. Psychiatry and Clinical Neurosciences Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and
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https://doi.org/10.1002/pcn5.41

2 of 3 | SEROTONIN SYNDROME BY ATOMOXETINE OVERDOSE
B A C K GR O U N D
Serotonin syndrome is a potentially life‐threatening condition
characterized by mental status changes (i.e., agitation and
confusion), autonomic hyperactivity (i.e., fever, tachycardia, and
diaphoresis), and neuromuscular abnormalities (i.e., myoclonus,
1,2
tremor, and hyperreflexia). This syndrome can be caused by
various medications that engender serotonergic overactivity
1,2
in the central and peripheral nervous systems. Serotonin
syndrome has been associated with widely various drug types,
such as antidepressants, monoamine oxidase inhibitors, psychos-
timulants, and opioids.1
Atomoxetine is a selective norepinephrine reuptake inhibitor
3
used to treat attention‐deficit hyperactivity disorder (ADHD). Two
case reports have described serotonin syndrome associated with
4,5
atomoxetine. However, these cases were induced by the combina-
tion of atomoxetine with venlafaxine5 or methylphenidate,4 leading
to the possibility that drugs other than atomoxetine might have
contributed to this syndrome. This report describes serotonin
syndrome induced solely by overdose of atomoxetine in a patient
with ADHD.
C A S E PRE S E NT A T I O N
The patient in this case was a 21‐year‐old man who had been
treated with atomoxetine 80 mg/day at a local psychiatric hospital
because of ADHD. No other medication had been administered.
He reported that he had never used illegal drugs, and that he had
rarely consumed alcohol. He provided written informed consent
for presentation of his clinical course. This report has been
approved by the Ethics Review Committee of Yamagata University
Faculty of Medicine.
The patient was transported to the emergency unit of our
hospital, 1 h after his intentional ingestion of 1200 mg of
atomoxetine in a suicide attempt. On admission, he showed
profuse diaphoresis, marked agitation, and somnolence. His body
temperature was 37.4°C, blood pressure 137/74 mmHg, heart
rate 135 beats/min, and corrected QT interval 0.604 s. Neurologi-
cal examinations revealed severe myoclonus, tremor, and hyper-
reflexia of the four limbs. The laboratory blood test results were
within normal levels except for increased levels of white blood
cells (23,240/μl) and blood sugar (239 mg/ml). He had metabolic
acidosis (pH = 6.880, PaCO2 = 55.0 mmHg, and HCO 3‐ = 10.1
nmol/L). Chest X‐ray showed no abnormality. He was diagnosed
as having serotonin syndrome according to the Sternbach
criteria.2 Administration of activated charcoal, massive infusion,
and conservative treatment were undertaken. Three days later,
serotonin syndrome symptoms had disappeared completely.
Blood test results were within normal limits. Seven days later,
he was discharged.
27692558, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pcn5.41 by Test, Wiley Online Library on [21/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
DIS CUSSION
Serotonin syndrome is caused by serotonergic drugs, which can
induce increased serotonin release, serotonin reuptake inhibition,
serotonin metabolism inhibition, serotonin‐1a receptors activation,
and serotonin‐2a receptors blockade.1 Earlier case reports have
described serotonin syndrome associated with atomoxetine, venla-
faxine,5 and methylphenidate4 co‐administered with atomoxetine.
Venlafaxine and methylphenidate have the respective effects of
serotonin reuptake inhibition6 and serotonin‐1a receptor activation.7
Therefore, the possibility cannot be excluded that venlafaxine or
methylphenidate other than atomoxetine contributed to serotonin
syndrome in these earlier cases. The case reported herein is the first
describing that atomoxetine alone induced serotonin syndrome.
Atomoxetine is a selective norepinephrine reuptake inhibitor.3
However, an in vitro study using radioligand binding assays for human
monoamine transporters showed that atomoxetine binds not only to
the norepinephrine transporter, but also to the serotonin transporter
to a lesser degree.6 A study using positron emission tomography in
monkeys also showed that atomoxetine at clinically relevant doses
occupies both norepinephrine and serotonin transporters.8 There-
fore, in the case presented herein, the effects of atomoxetine on the
serotonin transporter might have been caused by serotonergic
overactivity, developing thereafter into serotonin syndrome.
Earlier reports have suggested that atomoxetine overdose at up
to 1200 mg results in less severe toxicity and duration of the
symptoms after overdose resolves in less than 30 h.9,10 The patient in
our case displayed severe serotonin syndrome at a dose of
atomoxetine of 1200 mg. Moreover, his symptoms continued for
72 h after the overdose. These discrepancies suggest that our patient
had individual predisposition to atomoxetine toxicity. Atomoxetine
has been shown to be a substrate of cytochrome P450 (CYP) 2D6
and 2C193; genetic variants of CYP2D611 and 2C1912 are associated
with impaired metabolism of atomoxetine. Therefore, it is possible
that the patient in this case had genetic variants of CYP2D6 and/or
2C19. His genetically determined predisposition contributed to
serotonin syndrome.
CONCLUSION
In conclusion, results from this case suggest that atomoxetine can
cause serotonin syndrome, presumably via its effects of serotonin
reuptake inhibition. Clinicians should consider this syndrome induced
by atomoxetine overdose.
A UT H O R C O N T R I B U TI O NS
Fumika Sato, Akihito Suzuki, and Keisuke Noto treated the patient
and drafted the manuscript. Toshinori Shirata, Muneaki Kanno, Ryota
Kobayashi, and Koichi Otani critically reviewed the draft and revised
it. All authors approved the final version of the manuscript.

SEROTONIN SYNDROME BY ATOMOXETINE OVERDOSE
A C KN O W L E D G M E N T 5.
This case report did not receive any funding. We sincerely appreciate
the cooperation of the patient and his family.
6.
CO NFL I CT OF INTERES T
The authors declare no conflict of interest. 7.
D A TA A V A I L A B I L I T Y S T A T E M E N T
All relevant data are included in the paper. 8.
E T H I CS APP ROV AL S T A T E ME N T
Written informed consent for presentation of clinical course was
9.
given by the patient. This report has been approved by the Ethics
Review Committee of Yamagata University Faculty of Medicine.
10.
ORCID
11.
Toshinori Shirata http://orcid.org/0000-0002-9118-0363
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How to cite this article: Sato F, Suzuki A, Noto K, Shirata T,
Kanno M, Kobayashi R, et al. Serotonin syndrome induced by
overdose of atomoxetine alone in a patient with attention‐
deficit hyperactivity disorder: A case report. Psychiatry Clin.
Neurosci. Rep. 2022;1:e41. https://doi.org/10.1002/pcn5.41