History of Present Illness
A 22-year-old female, weighing 58.1 kg, with a medical history of major depressive disorder, anxiety, and alcohol use disorder, presented to the Emergency Department following an intentional overdose.
Earlier that evening, she texted her boyfriend, admitting to a suicide attempt. On arrival, she initially denied ingestion, but once detained for an unrelated legal matter, she confessed to taking:
30 tablets of hydroxyzine 25 mg (750 mg total)
10 tablets of venlafaxine XR 150 mg (1500 mg total)
Her prescribed medications include venlafaxine, trazodone, spironolactone, oral contraceptives, hydroxyzine, and albuterol (ProAir) as needed.
Clinical Presentation and Initial Evaluation
In the ED:
She was awake, alert, and oriented x3
Afebrile (98.1°F)
HR 90 bpm, later rising to 140 bpm
BP 139/99 mmHg
Oxygen saturation was 100% on room air
Pupils were normal at first
However, within a few hours, the patient deteriorated with:
Marked sinus tachycardia (HR 130–140s)
Seizure activity (treated with Ativan 2 mg)
Visual and auditory hallucinations
Profound tremulousness and agitation
Mydriasis
Rigidity, especially noted in chest tone
Hyperreflexia with ankle clonus
Confusion and disorientation
Excessive diaphoresis
Hypoglycemia (glucose 64 → 50 mg/dL)
Excessive thirst
A dose of metoprolol 2.5 mg IV was administered initially for tachycardia but was discontinued after toxicology consultation due to concern for unopposed alpha activity and hypotension risk in serotonin syndrome or sympathomimetic states.
Laboratory Data and Toxicology Results
Initial Labs :
Acetaminophen: Undetectable
Salicylate & Ethanol: Undetectable
Sodium: 138.0 mEq/L
Potassium: 3.7 mEq/L
Chloride: 102.0 mEq/L
Bicarbonate (CO₂): 28.0 mEq/L
Creatinine: 1.83 mg/dL (suggesting early AKI)
Glucose: 98.0 mg/dL
Follow-up Labs :
Glucose: 64 → 50 mg/dL (hypoglycemia; treated with D50)
Creatine Kinase (CK): 6294 units/L (indicative of rhabdomyolysis)
Bicarbonate (CO₂): 22.0 mEq/L
White Blood Cell Count: 11.3 x10³/uL
QTc interval: 410 ms
Urine drug screen: THC positive
Which toxidrome best fits the patient's clinical picture?
1.Anticholinergic Toxidrome
2. Serotonin Toxicity (Serotonin Syndrome)
3. Mixed Toxidrome
Reveal the answer
Substance Pharmacology
Venlafaxine XR (Effexor): An SNRI with strong serotonergic activity; in overdose, associated with seizures, tachycardia, serotonin syndrome, and rhabdomyolysis.
Hydroxyzine: An H1 receptor antagonist with significant anticholinergic properties at high doses (e.g., delirium, mydriasis, dry skin, urinary retention).
In this instance, the patient displayed several clinical signs, including delirium, mydriasis, diaphoresis, tremor, hyperreflexia or clonus, stiffness, seizures, rhabdomyolysis, hallucinations, and hypoglycemia, coupled with diaphoretic skin. Especially, QT prolongation was absent.
Delirium and mydriasis are non-discriminatory symptoms common in both anticholinergic and serotonin poisoning. But diaphoresis, which is rare in anticholinergic states—usually associated with dry skin—was notable here and supported serotonin poisoning. Likewise, especially when seen combined, tremors and hyperreflexia or clonus are classic indicators of serotonin toxicity and are uncommon in anticholinergic poisoning.
The presence of rigidity, especially axial rigidity, and seizures also fits serotonin syndrome, in which these symptoms are often seen. Furthermore, rhabdomyolysis and hypoglycemia are described, both of which are more common in serotonin poisoning and unusual in pure anticholinergic conditions.
While evident in this case, hallucinations are classic characteristics of anticholinergic toxicity, but can also develop, albeit less commonly, in serotonin syndrome. Since QT prolongation is a possible but non-specific finding in both toxidromes, its absence does not assist in distinguishing the two. At last, the patient had diaphoretic skin, which strongly supports serotonin overdose, as anticholinergic poisoning usually produces dry, flushed skin.
Given the prevalence of hyperreflexia, clonus, diaphoresis, tremor, rigidity, and rhabdomyolysis, the general clinical picture is considerably more consistent with serotonin toxicity even if a few markers (such as hallucinations) could indicate anticholinergic toxicity.
Related topic: Antipsychotics like aripiprazole and clozapine can contribute to serotonergic or anticholinergic presentations. Learn more in the [Aripiprazole Toxicity] and [Clozapine Toxicity] guides.
Interpretation
The presence of diaphoresis, rigidity, ankle clonus, hyperreflexia, seizure, rhabdomyolysis, and hypoglycemia strongly supports a diagnosis of serotonin toxicity. While hallucinations and mydriasis could initially suggest an anticholinergic toxidrome, the absence of dry skin, urinary retention, or hypoactive reflexes and the presence of neuromuscular hyperactivity make a pure anticholinergic syndrome unlikely.
A mixed toxidrome is plausible, but the predominant features—particularly clonus and rigidity—are pathognomonic for serotonin syndrome.
Therapeutic Decision-Making
Rivastigmine patch was initially considered for presumed anticholinergic features but was appropriately withheld once serotonin syndrome became clear.
Benzodiazepines (Ativan) were emphasized and escalated to sedate the patient effectively.
Phenobarbital was discussed as a backup sedative for severe serotonin syndrome if benzos were insufficient.
Beta-blockade (metoprolol) was advised against due to the risk of sympathomimetic toxidromes.
Conclusion
This case represents a serotonin syndrome precipitated by venlafaxine XR overdose, with some overlapping anticholinergic features from co-ingestion of hydroxyzine. The diagnostic challenge underscores the importance of recognizing clonus, hyperreflexia, diaphoresis, and rigidity as hallmark signs of serotonin toxicity.
Management was ultimately optimized by:
Recognizing serotonin syndrome as the primary driver
Avoiding inappropriate therapies (e.g., rivastigmine, beta-blockers)
Using escalating benzodiazepine doses to control CNS and neuromuscular symptoms
Monitoring for and treating complications such as rhabdomyolysis and hypoglycemia
Key Learning Points
Serotonin syndrome often presents with neuromuscular hyperactivity, unlike anticholinergic toxicity.
Clonus and rigidity are critical differentiators between toxidromes.
Hydroxyzine may add diagnostic confusion due to anticholinergic effects.
Management prioritizes benzodiazepines and supportive care; rivastigmine is inappropriate in serotonergic presentations.
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Authors:
Bio:
Dr. Omid Mehrpour (MD, FACMT) is a senior medical toxicologist and physician-scientist with over 15 years of clinical and academic experience in emergency medicine and toxicology. He founded Medical Toxicology LLC in Arizona and created several AI-powered tools designed to advance poisoning diagnosis, clinical decision-making, and public health education. Dr. Mehrpour has authored over 250 peer-reviewed publications and is ranked among the top 2% of scientists worldwide. He serves as an associate editor for several leading toxicology journals and holds multiple U.S. patents for AI-based diagnostic systems in toxicology. His work brings together cutting-edge research, digital innovation, and global health advocacy to transform the future of medical toxicology.
References:
Chiew AL, Holford AG, Chan BSH, Isoardi KZ. Rivastigmine for the management of anticholinergic delirium. Clin Toxicol (Phila). 2024 Feb;62(2):82-87. doi: 10.1080/15563650.2024.2319854. Epub 2024 Mar 11. PMID: 38465631.
Mikkelsen N, Damkier P, Pedersen SA. Serotonin syndrome-A focused review. Basic Clin Pharmacol Toxicol. 2023 Aug;133(2):124-129. doi: 10.1111/bcpt.13912. Epub 2023 Jun 20. PMID: 37309284.
