CASE REPORT

Serotonin Syndrome Following Combined Administration of
Dopaminergic and Noradrenergic Agents in a Patient With
Akinetic Mutism After Frontal Intracerebral Hemorrhage:
A Case Report
Dae Geun Jeon, MD,* Yong Wook Kim, MD, PhD,† Na Young Kim, MD,† and Jung Hyun Park, MD, PhD*

Background: Serotonin syndrome (SS) is a potentially life-threatening
condition that can be caused by use of proserotonergic drugs. Several studies have reported that combined administration of various medications may
induce SS. We report a case of SS in a patient who was being treated with
dopaminergic and noradrenergic drugs.
Case Presentation: A 55-year-old man with a right frontal intracerebral
hemorrhage extending to the left cerebral hemisphere presented with clinical features of akinetic mutism. Three months after onset, dopaminergic
(methylphenidate, levodopa/benserazide) and noradrenergic (atomoxetine)
drugs were administered to enhance his cognitive function. His cognitive
function gradually improved during 8 weeks of dose escalation. One day
after the dose of atomoxetine was increased from 40 mg/d to 60 mg/d,
the patient developed inducible clonus, rigidity, diarrhea, tachycardia,
and hyperthermia, in keeping with a diagnosis of SS. The symptoms and
signs suggestive of SS resolved on the day following cessation of all dopaminergic and noradrenergic drugs.
Conclusions: This case demonstrates that medications generally known
as dopaminergic or noradrenergic agents could have serotonergic effects
via a mechanism that is yet to be fully elucidated. The clinical manifestations of SS can be diverse, ranging from mild to severe and potentially fatal
symptoms. When administering a combination of catecholaminergic
agents, clinicians should carefully monitor the patient’s neurologic status
for unexpected adverse reactions.
Key Words: akinetic mutism, atomoxetine, levodopa, methylphenidate,
serotonin syndrome
(Clin Neuropharm 2017;00: 00–00)

S

erotonin syndrome (SS) may develop in circumstances of
overly increased serotonergic activity, which can be induced
by various proserotonergic medications.1 Serotonin syndrome is
a potentially life-threatening condition presenting as a spectrum
of clinical manifestations, including autonomic instability, neuromuscular abnormalities, and altered mental status.1,2 Although serotonin reuptake inhibitors are known to the most common
causative medications,1,3 several other medications with potential
serotonergic activity can also induce SS.1,2,4,5 There are some case
reports mentioning SS caused by dopaminergic agents that might
have serotonergic properties.6,7 However, to date, there has been
*Department of Rehabilitation Medicine, Gangnam Severance Hospital, Rehabilitation Institute of Neuromuscular Disease, and †Department and Research
Institute of Rehabilitation Medicine, Yonsei University College of Medicine,
Seoul, Republic of Korea.
Address correspondence and reprint requests to Na Young Kim, MD,
Department of Rehabilitation Medicine, Yonsei University College of
Medicine, 50-1 Yonsei-ro Seodaemun-gu, Seoul 120-752, Republic of
Korea; E‐mail: kny8452@yuhs.ac
Conflicts of Interest and Source of Funding: The authors have no conflicts of
interest to declare.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/WNF.0000000000000220

Clinical Neuropharmacology • Volume 00, Number 00, Month 2017

no report of coadministration of dopaminergic and noradrenergic
agents causing SS.
Dopaminergic and noradrenergic agents have been proven to
improve neuropsychiatric outcomes in patients with acquired
brain injury.8,9 Previous studies have shown that dopaminergic
agents have an important role in recovery of cognition and improvement of motor and mood deficits.8 Administration of a noradrenergic agent can also improve attention deficit and cognitive
skills after brain injury.10 In particular, recent research has identified that both types of agents are effective in akinetic mutism
(AM),11,12 which is caused by damage to bilateral frontal lobe.13
We report on a patient who experienced SS after dopaminergic14 and noradrenergic15 agents were administered to treat AM
resulting from a frontal intracerebral hemorrhage.

CASE REPORT
A 55-year-old, right-handed man had a right frontal intracerebral hemorrhage compressing the left frontal lobe (Fig. 1A)
for which he underwent a craniotomy and removal of the
hemorrhage (Fig. 1B). Three months after his hemorrhagic
stroke, the man was referred to our hospital for rehabilitation.
His score on the JFK Coma Recovery Scale (JFK-CRS)16 was
15/23. His eyes moved toward a target stimulus, but he lay
without moving or any verbal output and was unresponsive to
commands. A fluorodeoxyglucose positron emission tomography
scan of the brain revealed severely decreased brain metabolism in
the frontal cortices bilaterally (Fig. 1C). These clinical features
and functional neuroimaging findings suggested AM.
Dopaminergic agents (methylphenidate and levodopa/
benserazide) were administered to improve the patient’s cognitive
function.11,17 Methylphenidate was started at a dose of 10 mg/d
and gradually increased to 40 mg/d over 5 weeks. Levodopa/
benserazide was started at 100/25 mg and increased to 450/
112.5 mg/d over 5 weeks. Atomoxetine, classified as a selective
norepinephrine reuptake inhibitor,18 was added, given the recent
reports that atomoxetine is effective in AM because of its noradrenergic activity.13,19 Atomoxetine was started at 10 mg/d and increased in
increments to 40 mg/d over the 5-week period. With increasing doses
of these drugs, the patient’s cognition improved steadily.
On day 28 of his admission, the patient started to regain voluntary arm movements and could manipulate objects. By day 33,
he could walk independently. His JFK-CRS score had improved
to 17/23.
On day 55 of admission, the daily dose of atomoxetine was
increased to 60 mg. The next day, 5 hours after administration of
atomoxetine, the patient developed diaphoresis and fever. His
body temperature at this time was 38.2°C. Tachycardia (126
beats/min) and hypertension (150/97 mm Hg) were present. The patient had diarrhea throughout the day, and his bowel sounds were
slightly hyperactive. He also appeared agitated. On neurologic
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Clinical Neuropharmacology • Volume 00, Number 00, Month 2017

Jeon et al

FIGURE 1. A, Initial brain computed tomography. Right frontal intracerebral hemorrhage compressed left frontal lobe. B, Postoperative brain
computed tomography 2 months after stroke onset. Cortical defects in the territory of the bilateral anterior cerebral arteries are shown. C,
Brain fluorodeoxyglucose positron emission tomographic images 4 months after stroke onset. Decreased glucose metabolism in the bilateral
frontal lobes can be seen.

examination, he had inducible clonus and tremors in both upper extremities. Rigidity was observed in both the upper and lower extremities. These clinical manifestations represented 4 major and 2
minor symptoms in Radomski criteria20 for SS.
On day 56 of his admission, despite reducing the dose of
atomoxetine from 60 mg to 40 mg and adding an antihypertensive
agent, the patient’s blood pressure remained high (170/
101 mm Hg), and the tachycardia persisted. The laboratory and radiological findings did not show any abnormality except for a
mildly elevated white blood cell count of 11,870/μL (reference
range, 4000–10,800/μL). Hemoglobin was 12.0 g/dL (reference,
>13.0 g/dL), C-reactive protein, 0.9 mg/dL (reference, <1.0 mg/
dL); aspartate aminotransferase, 24 IU/L (reference range,
13.0–34.0 IU/L); alanine aminotransferase, 18 IU/L (reference
range, 5.0–46.0 IU/L); serum creatinine, 0.56 mg/dL (reference
range, 0.68–1.19 mg/dL); and urine white blood cell count was
0 to 2 per high-power field (reference range, 0–2 per high-power
field). We repeated the laboratory tests and chest radiographs for
2 days, but no further abnormal findings were found. The patient’s
level of consciousness was not changed, and his JFK-CRS was
maintained at 17/23. We discontinued the 2 dopaminergic agents
(methylphenidate and levodopa/benserazide) and atomoxetine
on the following day.
One day after stopping catecholamine stimulants, the patient’s blood pressure and pulse rate recovered to 140/80 mm Hg
and 90 beats/min, respectively. On day 60 of his admission, the patient’s symptoms of diaphoresis, tremor, and rigidity had disappeared, and his vital signs remained normal.

DISCUSSION
In the central nervous system, serotonin neurons are located
mainly in the brainstem and project axons to the forebrain and
midbrain.21 Serotonin neurons have multiple functions, including
regulation of mood, body temperature, the sleep cycle, and muscle
tone.22 Therefore, SS can be expressed in the form of various
symptoms and with varying degrees of severity. When mild, SS

2

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may manifest as akathisia, increased bowel movements, slight
tremor, and mydriasis.1,23,24 Patients with moderate SS may show
altered mental status, inducible clonus, mild hyperthermia, and
high blood pressure.1,23 In severe cases, these symptoms may
worsen and become life-threatening.1,23 Inducible clonus has been
regarded as the most important clue to establish a diagnosis of
SS.1,25 Our patient presented with tremor, rigidity, high blood
pressure, diarrhea, mild hyperthermia, and inducible clonus. This
case was considered to be a moderate case of SS.
The differential diagnosis for SS includes malignant hyperthermia, neuroleptic malignant syndrome, and overdosing of anticholinergics.1 For a correct diagnosis, the recommendation is
careful assessment of medication history and evaluation of clinical
symptoms.24 Our patient had several features suggestive of neuroleptic malignant syndrome, including hyperthermia, tremor,
tachycardia, and diaphoresis.26,27 However, unlike neuroleptic
malignant syndrome,26 these symptoms were not caused by
antidopaminergic agents or withdrawal of dopaminergic drugs.
Furthermore, there was no elevation of creatine phosphokinase
on laboratory testing, which is a usual finding in neuroleptic malignant syndrome resulting from rhabdomyolysis.26,27 In addition,
as in previous reports,2,7 the neurologic and autonomic symptoms
attributable to SS disappeared completely within 48 hours after
discontinuation of the culprit medications.
Seven types of serotonin receptor (5-HT1 to 5-HT7) have
been identified to date.1,28 Previous studies have suggested that
SS develops mainly in response to overstimulation of 5-HT1A receptors1,2,29,30 and possibly 5-HT2A receptors.23,30 Serotonin receptors can be overstimulated in a variety of ways, including
excessive levels of precursors, increased release of serotonin, decreased reuptake of serotonin, and slowed metabolism.2,15,23 A
number of drugs and drug combinations may cause SS.1,23,24
There have been a small number of case reports of SS caused
by administration of a combination of dopaminergic agents.
Sandyk6 described a case of SS in a patient with parkinsonism
treated with a combination of carbidopa and levodopa with bromocriptine. Avarello et al31 reported a case of SS induced by
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Clinical Neuropharmacology • Volume 00, Number 00, Month 2017

combined administration of a selective serotonin reuptake inhibitor and
levodopa. However, there are no reports of SS induced by combined administration of dopaminergic and noradrenergic agents.
In the present case, it is difficult to determine the critical factor contributing to SS. Methylphenidate not only facilitates dopaminergic transmission, but also presumably has strong serotoninreleasing activity and high affinity for 5-HT1A and 5-HT2B receptors.32 A recent study found that levodopa stimulates exocytosis
of serotonin, leading to elevation of extracellular concentrations
of serotonin.33 Atomoxetine has been shown to have high affinity
for both norepinephrine and serotonin receptors in vivo15,34 and
could produce signs of SS by stimulating 5-HT receptors.4 Serotonin syndrome might be induced by accumulating doses or the
synergistic actions of these medications.
Our findings suggest that medications commonly regarded
as catecholaminergic agents could affect serotonin receptors by
various mechanisms that are as yet not completely revealed. Moreover, these medications could lead to a potentially life-threatening
iatrogenic condition associated with overstimulation of central serotonin receptors. All physicians should be aware of this potentially fatal adverse effect of catecholaminergic agents.
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