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Abstract

Serotonin syndrome (SS) and hyponatremia are severe, potentially life-threatening adverse reactions to serotonergic medications. Their concurrent manifestation is rare but clinically significant due to overlapping pathophysiological mechanisms. This report describes the fatal outcome of a 30-year-old female who presented to the Emergency Department with agitation following self-administration of duloxetine 60 mg, in addition to ongoing amitriptyline therapy and possible L-tryptophan supplementation. During hospitalization, she was treated with intravenous chlorphenamine for a suspected allergic reaction. Subsequently, she developed severe neurological deterioration, malignant arrhythmia, and profound acute hyponatremia (serum sodium 114 mmol/L), culminating in brain death within 48 h. The synergistic pharmacodynamic and pharmacokinetic interactions between duloxetine, amitriptyline, and chlorphenamine—three agents with serotonin reuptake inhibition properties—were implicated in precipitating SS and syndrome of inappropriate antidiuresis (SIAD)-induced hyponatremia. This combination resulted in extensive cerebral edema and cardiopulmonary arrest. The case highlights the diagnostic challenge posed by overlapping SS and hyponatremia manifestations, particularly when compounded by incomplete pharmacological histories and inappropriate drug administration. Clinicians should maintain high vigilance for SS and hyponatremia in patients receiving serotonergic agents, especially when multiple such drugs are co-administered. Comprehensive medication anamnesis, prompt electrolyte monitoring, and avoidance of pharmacodynamic duplication are essential to prevent similar outcomes.

Keywords

contraction band necrosis hyponatremia myelinolysis serotonin syndrome syndrome of inappropriate antidiuresis

Introduction

Serotonin syndrome (SS) and hyponatremia are two well-recognized, potentially life-threatening complications of antidepressant therapy. SS arises from increased serotonergic activity in the central and peripheral nervous system. It is most commonly associated with the combination of two serotonergic agents, but can also occur after the initiation or dose escalation of a single drug in particularly sensitive patients.^1,2 It usually develops within 24 h of a dosage change or initiation of a serotonergic agent, most often within the first 6 h.³

Selective serotonin reuptake inhibitors (SSRIs) are the drug class most commonly implicated in SS, although serotonin–norepinephrine reuptake inhibitors (SNRIs; e.g., duloxetine and venlafaxine) may carry a slightly higher risk.⁴

Excessive serotonin at the synaptic cleft overstimulates postsynaptic 5-HT1A and 5-HT2A receptors, leading to a wide spectrum of manifestations—from agitation, tremor, and hyperreflexia to severe hyperthermia, rigidity, and multiorgan failure.⁵

Clinically, SS is characterized by the triad of altered mental status (anxiety, agitation, confusion), autonomic instability (hyperthermia, diaphoresis, tachycardia, hypertension), and neuromuscular hyperactivity (tremor, myoclonus, hyperreflexia, and rigidity).⁶ Unless recognized and treated promptly, SS can ultimately lead to seizures, shock, and death.^1,7

The clinical course of SS shows marked interindividual variability, likely influenced by genetic factors such as cytochrome P450 polymorphisms, as well as variations in the serotonin transporter (SERT) and serotonin receptor polymorphisms.^5,8

There is no definitive diagnostic test for SS, as serum serotonin levels do not reflect clinical severity; thus, diagnosis is clinical. The most widely used tool is the Hunter Toxicity Criteria,⁹ which require prior serotonergic exposure plus at least one specific clinical feature: (i) spontaneous clonus; (ii) inducible clonus plus agitation or diaphoresis; (iii) ocular clonus plus agitation or diaphoresis; (iv) tremor plus hyperreflexia; (v) hypertonia plus a temperature above 38°C plus ocular or inducible clonus.

The Hunter criteria are recommended as the gold standard for diagnosing SS; however, recent studies have highlighted some limitations,¹⁰ including the occurrence of SS without hyperthermia and variable onset times.

Antidepressants are also associated with hyponatremia, defined as serum sodium (Na⁺) < 135 mmol/L and linked to higher mortality when levels fall below 125 mmol/L.^11,12

Acute hyponatremia develops when (i) water intake exceeds renal excretory capacity, (ii) arginine vasopressin (AVP) is inappropriately released, as in the syndrome of inappropriate antidiuresis (SIAD) which encompasses the classic syndrome of inappropriate antidiuretic hormone secretion (SIADH),¹³ or (iii) renal water reabsorption is abnormally enhanced, as in nephrogenic syndrome of inappropriate antidiuresis.¹⁴

Clinically, acute hyponatremia manifests with neurological symptoms ranging from fatigue, tremor, and confusion to seizures, coma, and death, particularly when serum sodium levels fall abruptly below 120 mmol/L.^11,15 Consequently, acute hyponatremia constitutes a medical emergency that requires carefully controlled correction with hypertonic saline to reverse osmotic injury and cerebral edema¹⁶ while preventing osmotic demyelination.¹⁷

Both SS and acute hyponatremia may be induced by SSRIs/SNRIs,^15,18
–20 with their common pathophysiological pathway considered to be the development of SIAD.²¹

The case presented concerns the fatal event of a young woman during an Emergency Department (ED) visit, caused by encephalopathy and malignant arrhythmia secondary to acute hyponatremia. The electrolyte imbalance developed after intravenous administration of chlorphenamine, a drug used for its antihistaminic properties, but also acts on SERT. The purpose of this inappropriate administration was to treat symptoms that had appeared in the patient following the use of antidepressants.

This report aims to describe the clinical presentation and pathophysiological mechanisms of this fatal case, highlighting the diagnostic challenges posed by the overlapping manifestations of SS and SIAD-induced hyponatremia, and to underscore the importance of comprehensive pharmacological assessment and monitoring in similar clinical scenarios.

Case report

A 30-year-old female patient presented to the ED with generalized burning sensations after ingesting a single 60 mg tablet of duloxetine. Her recent medical history was notable for vaginal burning, dysuria, urinary frequency, and nocturia, with urodynamic studies revealing signs of detrusor-sphincter dyssynergia, for which several pharmacological treatments had previously been attempted (Table 1).

Table 1.

Pharmacological treatments administered before ED admission.

Drug	Dosage	Start date	End date
Amitriptyline	Up to 24 mg/day	2 months prior	Ongoing
Buprenorphine patch	5 mg/week	2 months prior	Suspended (date unclear)
Red Cranberry, Goldenrod, Vitamin C, Vitamin B12 (supplement)	Unspecified	2 months prior	Discontinuation unclear
Magnesium bisglycinate, Boswellia, L-tryptophan (supplement)	Magnesium bisglycinate 225 mg, Boswellia 175 mg, L-tryptophan 150 mg	2 months prior	Discontinuation unclear
Eperisone	Unspecified	5 days prior	Ongoing
Cyclobenzaprine	10 mg/day	3 days prior	Discontinuation unclear
Duloxetine	60 mg (single dose)	Day of ED admission	Single administration

ED, Emergency Department.

The therapy preceding the ED admission consisted of amitriptyline at a dose of 24 mg/day and eperisone at an unspecified dosage. In the hours immediately preceding presentation, a single oral dose of duloxetine 60 mg was administered. The information regarding the use or discontinuation of the supplement containing L-tryptophan remains unavailable.

Upon arrival at the ED at 13:31, the patient was alert, cooperative, and eupneic, but exhibited marked agitation. The triage assessment classified her condition as moderately critical (yellow code). Initial vital signs were heart rate 110 beats per minute (bpm), blood pressure 126/80 mmHg, body temperature 36.5°C, and oxygen saturation 99% on room air.

Laboratory investigations revealed normal values for red blood cells, leukocytes with differential within normal limits, platelets, bilirubin, transaminases, amylase, gamma-glutamyl transferase, creatinine, and C-reactive protein. Blood glucose was 114 mg/dL; serum sodium 132 mEq/L; potassium 3.8 mEq/L; and chloride 97 mEq/L.

An electrocardiogram (ECG) obtained on admission revealed sinus tachycardia at 98 bpm, without additional abnormalities, and with a normal corrected QT Interval (QTc).

Based on the reported symptoms, the provisional diagnosis was a drug-induced allergic reaction. Initial treatment, initiated at 13:34, consisted of intravenous (IV) administration of chlorphenamine (10 mg, 1 vial IV) and methylprednisolone (40 mg, 1 vial IV).

At 15:20, a follow-up ECG demonstrated persistent sinus tachycardia at 96 bpm, without additional abnormalities and with a normal QTc interval.

Approximately 3.5 h post-admission (PA), the patient became agitated and absconded from the ward. She was later found collapsed in the hospital parking lot, exhibiting tremors and rigidity. She was subsequently returned to the ED, where she received intravenous diazepam 5 mg bolus and a continuous infusion of 10 mg (administered at 17:59).

The patient was accompanied and assisted by her husband, who reported that she experienced episodes of intense internal heat, prompting her to undress, as well as episodes of profuse urinary output. Around 19:00, the husband requested medical assistance due to a further episode of significant urine loss.

At 20:31 (6.5 h PA), the patient was administered 500 mL of 0.9% saline solution for rehydration. Vital signs at that time were: heart rate 78 bpm (regular rhythm), blood pressure 125/80 mmHg, oxygen saturation 98% on room air, and respiratory rate 12 bpm. No cardiorespiratory monitoring was initiated.

Around 21:00 (approximately 7.5 h PA), the husband alerted the medical staff as the patient appeared rigid and exhibited excessive salivation.

Clinical records indicate that, at 22:00 (8.5 h PA), the patient experienced cardiac arrest. Resuscitation measures were promptly initiated, including orotracheal intubation, cardiopulmonary resuscitation, and defibrillation. Atrial flutter was documented on ECG. After several electrical shocks (125, 200, and 300 Joules), the sinus rhythm was successfully restored.

Subsequent echocardiography revealed a globular left ventricle with hypokinesia of the interventricular septum and an ejection fraction of 40%, without evidence of pericardial effusion.

At 23:37 (approximately 10 h PA), arterial blood gas analysis revealed severe metabolic acidosis (pH 7.265; actual bicarbonate 16.9 mmol/L; standard bicarbonate 17.2 mmol/L), associated with an elevated anion gap of 17 mmol/L and hypo-osmolality (measured osmolarity 242.5 mOsm/kg). Electrolyte disturbances included severe hyponatremia (Na⁺ 114 mmol/L), hypokalemia (K⁺ 3.0 mmol/L), hypocalcemia (ionized Ca²⁺ 1.01 mmol/L), and hypochloremia (Cl⁻ 83 mmol/L).

Corrective treatment with 3% hypertonic saline infusion was promptly initiated.

Laboratory tests on peripheral venous blood drawn at 01:00 the following day (approximately 11.5 h PA) confirmed severe hyponatremia (122 mEq/L), mild hypokalemia (3.0 mEq/L), and mild hypochloremia (88 mEq/L).

At 07:56 (18.5 h PA), a non-contrast computed tomography (CT) scan demonstrated diffuse cerebral edema and subtle pontomesencephalic hypodensity (Figure 1).

Figure 1.

Non-contrast CT demonstrating diffuse cerebral edema, pontomesencephalic hypodensity, and absence of cerebral circulation.

A toxicological screening (20 h PA) revealed tricyclic antidepressant levels of 46.9 ng/mL (reference: 50–100 ng/mL) and benzodiazepine levels of 89.8 ng/mL (reference: positive > 50 ng/mL). Urinary screening was negative for carbamazepine, phenobarbital, phenytoin, opioids, cocaine, methadone, cannabinoids, amphetamines/methamphetamines, and MDMA.

Multiplex assay on cerebrospinal fluid (CSF) and respiratory samples was negative for all bacterial, viral, and fungal targets. CSF was clear and colorless, with glucose 0.80 g/L (CSF/serum ratio 59%), proteins 73 mg/dL, and albumin 43.5 mg/dL (albumin index 11). Cytology revealed 1000 erythrocytes/µL, with preserved morphology

Despite intensive care, the patient remained comatose with bilaterally fixed and dilated pupils. Brain death was confirmed 2 days after admission.

An autopsy and histological examination were performed, but yielded no significant findings sufficient to determine the precise manner of death.

At gross examination, the brain was normal in shape and size, with slightly reduced weight and moderately reduced consistency. Although it appeared morphologically normal and symmetric, it showed signs of congestion and edema. The midbrain, pons, and medulla oblongata showed no clear macroscopic pathological alterations. Consequently, the entire brain was fixed in formalin for further macroscopic and microscopic examination. Upon dissection of the brainstem, areas of grayish color were noted at the base of the pons, surrounded by brain tissue of normal morphology and color (Figure 2).

Figure 2.

Gross examination of the brain fixed in formalin, showing areas of grayish discoloration at the base of the pons.

The samples underwent H&E staining. Histological examination of the brain showed edema of white matter and acute congestion of the parenchymal vessels. In the brain and brainstem, there were findings of pericellular and perivascular edema. Deeper within the brainstem, reduced cellularity was noted, accompanied by optically empty vacuoles in the parenchyma, sparse representation of nervous cells, numerous reactive glial cells, and occasional perivascular macrophages and small lymphocytes. Intense blood stasis was also evident in the region. Subsequent Luxol Fast Blue staining, which targets myelin, revealed areas of reduced parenchymal staining with a symmetrical distribution in the central regions of the brainstem, midbrain, and pons. The staining also showed diffuse rarefaction of neurofibrils and several optically empty areas disrupting the nerve sheaths. In addition, an abundance of reactive glial cells surrounded by large optically empty vacuoles was appreciable (Figure 3).

Figure 3.

Histopathological findings in the brainstem showing diffuse rarefaction of neurofibrils and several optically empty areas disrupting the nerve sheath (Luxol Fast Blue, ×20).

The heart was normal in shape and size, with slightly reduced weight and moderately reduced consistency, measuring 13 × 9 × 5 cm. The left ventricular wall was 2.0 cm thick, the interventricular septum measured 1.7 cm, and the right ventricular wall was 0.4 cm. The atrioventricular and arterial valves appeared normal. The coronary ostia were patent, and the coronary arteries showed a regular caliber, normally thickened walls, and patent lumen throughout their course.

Cardiac histology revealed sarcomeric fibers with signs of tetany, evidenced by shortening of the Z-lines, microhemorrhages, and fragmentation due to rupture. The cardiomyocyte nuclei appeared to populate the fibers, showed polymorphic volume, and contained finely dispersed chromatin in granules and/or clumps (Figure 4). Some degree of homogenization was also observed in the papillary muscles in certain sections examined. In the right ventricular wall, adipose lobules between fibrocellular bundles were noted.

Figure 4.

(a) Intense hyperesinophilia of the hypercontracted myocardial cells with rhexis of the myoﬁbrillar apparatus into cross-ﬁber, anomalous, and irregular or pathological bands. The latter are formed by segments of hypercontracted sarcomeres with scalloped sarcolemma (black arrow) (H&E, ×150). (b) Fragmentation of the whole myocell (pancellular lesion), which ranges from early breakdown in pathological bands to a total granular disruption (white arrow) (myoﬁbrillar degeneration; Masson Trichrome, ×100).

Subsequent analyses on blood samples collected 2 days PA, performed by GC-MS (Total Ion and SIM modes) and confirmed by LC-MS/MS, excluded the presence of duloxetine and amitriptyline. No further toxicological tests were conducted, as second-day analyses were negative, and no clinical history suggested substance abuse.

Review of clinical documentation suggested that the primary lethal event was severe acute hyponatremia. However, it remained unclear whether the acute hyponatremia initially precipitated ventricular fibrillation leading to extensive cerebral edema or whether the cerebral edema itself induced fatal cardiac arrhythmia via vagal reflexes affecting heart rate and conduction.

Neurological symptoms during the ED admission—characterized by agitation, rigidity, sialorrhea, profuse urinary output, and probable convulsive episodes—were pathophysiologically intertwined and could be attributed to both SS and hyponatremia secondary to SIAD.

Discussion

This case underscores the diagnostic challenges inherent in complex pharmacological interactions and highlights the risks associated with incomplete medication histories and the administration of potentially hazardous drugs without a thorough understanding of their interactions. On the day of admission to the ED, the patient was simultaneously exposed to three agents known to inhibit serotonin reuptake—and, to a lesser extent, norepinephrine reuptake—namely amitriptyline and duloxetine, both self-administered at home, and chlorphenamine, administered in the ED for a suspected drug-induced allergic reaction. In addition, it remained unclear whether the patient continued taking an L-tryptophan supplement, further complicating the assessment of serotonergic burden.

Regarding the latter, the global regulation of L-tryptophan is heterogeneous: some countries impose restrictions on the maximum allowable dosage, whereas in most cases, including Italy, no official limits have been established.^22,23

Chlorphenamine is a first-generation alkylamine H1-antihistamine indicated for the symptomatic treatment of allergic reactions. Beyond its antihistaminic activity (H1 Ki = 1.4 nM,²⁴ it also exhibits selective inhibition of SERT (Ki = 15.2 nM),²⁵ functionally aligning its pharmacodynamic profile with that of SSRIs.²⁶

Duloxetine, an SNRI, has high affinity for SERT (Ki = 0.8 nM) and moderate affinity for the norepinephrine transporter (NET) (Ki = 7.5 nM).^27,28

Amitriptyline, a tricyclic antidepressant, is a tertiary amine with moderate binding affinity for SERT (Ki = 3.45 nM), NET (Ki = 13.3 nM),¹⁸ and histaminergic receptors (H1 Ki = 0.5 nM, H4 Ki = 7.31 nM).²⁹ Its receptor-mediated actions confer both antidepressant and analgesic effects.³⁰

Importantly, all three agents undergo metabolism via the CYP2D6 pathway, which is inhibited by duloxetine, thereby increasing serum levels of amitriptyline and chlorphenamine and enhancing their toxic effects.

This combination likely precipitated a toxic serotonergic state that rapidly evolved into acute hyponatremia,³¹ as suggested by the Naranjo score indicating a probable adverse drug reaction.³²

The clinical course was complicated by progressive neurological decline and ventricular fibrillation. Laboratory tests confirmed acute hyponatremia, and CT imaging demonstrated extensive brainstem edema, with histology revealing myelin sheath damage.¹⁷

This case emphasizes that in patients presenting with adverse effects related to antidepressant use—even in acute settings—both SS and SIAD-induced hyponatremia should be thoroughly investigated. Although drug-induced hyponatremia often develops over time,³³ this case demonstrates that, when overlapping with serotonin toxicity, it can arise rapidly and with life-threatening severity.

The clinical presentation of these conditions may be ambiguous due to overlapping neurological manifestations. While hyponatremia often causes muscle weakness with hyporeflexia, SS typically presents with hyperreflexia and clonus.³⁴ Nonetheless, both can manifest with symptoms ranging from mild (e.g., fatigue, lethargy, dizziness, and muscle cramps) to moderate (e.g., confusion, rigidity, and tremors), and even severe neurological complications such as ataxia, aphasia, seizures, and coma.³⁵ Comprehensive medication reconciliation and an in-depth understanding of the pharmacodynamics of prescribed drugs are thus mandatory.

In this case, the intravenous administration of 10 mg chlorphenamine added an SERT inhibitor to two agents already present, one of which—duloxetine—had been administered at a full therapeutic dose of 60 mg. This combination likely precipitated the onset of both SS and SIAD-induced hyponatremia, ultimately leading to a fatal outcome.

To the best of our knowledge, no fatal cases of chlorphenamine-induced hyponatremia have been reported in the literature, nor is hyponatremia among its known adverse effects.³⁶ Chlorphenamine is, however, recognized for its cardiotoxic potential, including QT prolongation and an increased risk of torsades de pointes,³⁷ primarily through interference with potassium ion channel activity.³⁸ While most reported cases involve overdose,³⁹ instances have occurred at therapeutic doses, likely due to poor CYP2D6 metabolizer status.⁴⁰ In the present case, however, approximately 2 h after administration, the QTc interval remained below 430 ms.

Regarding duloxetine, while chronic hyponatremia is a known risk,^20,41 acute hyponatremia following a single dose has also been reported. Yoshida et al.⁴² described a 77-year-old woman developing hyponatremia (from 135 to 119 mEq/L) and confusion on the second day after a single duloxetine dose, without fever, blood pressure changes, cardiac rhythm abnormalities, or hypoxemia. Other cases include hyponatremic encephalopathy 4 days after initiation,⁴³ and mild SIADH presenting as nausea within 2 days.⁴⁴ Individual susceptibility appears to involve mechanisms including plasma protein binding interactions and CYP1A2 and CYP2D6 activity.²⁸

In the present case, duloxetine—being a CYP2D6 inhibitor—likely contributed to increased plasma levels of amitriptyline and chlorphenamine. Furthermore, compared with the mild clinical features described in other cases of duloxetine-induced hyponatremia, the patient in the present case exhibited, at admission to the ED, a clinical picture more consistent with serotonin toxicity, with normal electrolyte levels. Although uncommon, the association between SS and hyponatremia has been reported in the literature in cases of overdose^45,46 or when two antidepressants are combined.⁴⁷ A distinctive feature of this case is that the fatal event occurred not from drugs prescribed for mental disorders but from medications used for analgesia (duloxetine and amitriptyline) and to manage their adverse effects (chlorphenamine), leading to a rapidly fatal outcome. Moreover, this occurred in a young patient, whereas antidepressant-induced hyponatremia is more commonly reported in older adults.¹⁹ Female gender, on the other hand, appears to be linked to a higher risk of developing hyponatremia and hyponatremic encephalopathy while on an SSRI,⁴⁸ possibly due to hormonal influences.

Estrogens impair astrocyte volume regulation and modulate hippocampal aquaporin-4 expression, thereby affecting water balance and neurotransmission.^49,50 Furthermore, interleukin-6 (IL-6), released after skeletal muscle injury and present at higher levels in women, promotes AVP secretion while reducing aquaporin-2 expression, impairing free water excretion.⁵¹ Thus, gender differences may influence not only the risk but also the severity and mortality of hyponatremic encephalopathy, in addition to the rate and extent of sodium decline.^52,53

Regarding the limitations of this report, information on L-tryptophan continuation is lacking, preventing a full assessment of serotonergic burden. AVP levels were not measured, so the SIAD subtype could not be determined. Continuous cardiorespiratory monitoring was not performed, limiting insight into possible arrhythmias before cardiac arrest.^54
–57 Toxicology for duloxetine and amitriptyline was negative, but the sample was collected 2 days after intake, reducing quantification accuracy. No pharmacokinetic or genetic testing (e.g., CYP2D6 genotyping) was performed to assess metabolic variability. The exact sequence leading to death—whether hyponatremia-induced cerebral edema triggered arrhythmia or resulted from cardiac arrest—remains speculative. Finally, clinical decisions and drug administration are interpreted retrospectively, introducing potential bias.⁵⁸

Conclusion

This report highlights the lethal potential of combining serotonergic drugs, which can lead to simultaneous SS and acute hyponatremia. Whenever possible, combinations of multiple serotonergic agents, including medications with ancillary serotonin reuptake inhibition such as chlorphenamine, should be avoided. If combination therapy is necessary, close monitoring for early signs of serotonin toxicity and hyponatremia is essential.

Detailed pharmacological histories, continuous neurological and electrolyte monitoring, and awareness of atypical presentations are critical for early recognition and intervention. Patients on SSRIs or SNRIs should be advised to consult their physician before taking any over-the-counter medications. Further research into pharmacogenetic predispositions and optimal diagnostic strategies for overlapping serotonin syndrome and SIAD is warranted to help prevent similar outcomes.⁵⁹

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Vittorio Fineschi

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