Situation: A 46-year-old woman with major depressive disorder has had little improvement after several months of treatment. Her psychiatrist plans to switch her from fluoxetine 20 mg daily to phenelzine, a monoamine oxidase inhibitor (MAOI). Four weeks after starting phenelzine, she takes an over-the-counter cough syrup containing dextromethorphan. Six hours later she is agitated and sweating, with hyperreflexia, inducible ankle clonus, dilated pupils, and diarrhea. Temperature is 38.4 °C, pulse 118/min, and blood pressure 158/96 mmHg. She has a mild frontal headache and no neck stiffness. Which condition is MOST likely?

Dextromethorphan is serotonergic, and combining it with an MAOI can cause serotonin syndrome, which begins within hours. The neuromuscular signs (hyperreflexia and inducible clonus) with dilated pupils, diarrhea, and hyperthermia distinguish it from neuroleptic malignant syndrome and from the severe occipital headache and stiff neck of an MAOI hypertensive crisis.

Core Mechanism
The clinical picture is a hyper-serotonergic toxidrome. Dextromethorphan increases intrasynaptic serotonin, and phenelzine blocks monoamine oxidase, the enzyme that would normally break down serotonin. When these two are combined, synaptic serotonin rises rapidly, producing a dose-related toxicity that is now understood as serotonin syndrome rather than a vague “drug interaction” ^[3]. The onset within 6 hours of dextromethorphan ingestion fits the expected time course for serotonergic excess.

Why This Is Serotonin Syndrome
The defining features of serotonin toxicity are clonus, hyperreflexia, hyperthermia, and agitation ^[3]. This patient shows inducible ankle clonus, hyperreflexia, a temperature of 38.4 °C, and agitation. The dilated pupils and diarrhea are additional autonomic and gastrointestinal signs of serotonergic overstimulation. The combination of neuromuscular excitability with autonomic instability and altered mental status is the classic triad of serotonin syndrome.

The dextromethorphan–MAOI interaction is well recognized. Case reports describe severe serotonin syndrome when dextromethorphan is combined with MAOI-containing substances, including progression to acute respiratory failure ^[1]. Although ayahuasca is a botanical MAOI source rather than pharmaceutical phenelzine, the pharmacologic principle is identical: MAO inhibition removes the primary degradation pathway for serotonin, so any added serotonergic agent can precipitate toxicity. A separate case involving phenelzine and sertraline showed a similar rapid onset — within 3 hours — of elevated temperature, pulse, labile blood pressure, and rigidity ^[2]. The shared mechanism across different serotonergic drug combinations supports the diagnosis here.

Distinguishing From the Other Options

Condition	Key features	Why it does not fit
Serotonin syndrome	Clonus, hyperreflexia, agitation, diarrhea, dilated pupils, hyperthermia; onset within hours of serotonergic drug	Matches all findings and timing
Neuroleptic malignant syndrome	Lead-pipe rigidity, bradykinesia, hyporeflexia, fever; onset over days; linked to dopamine blockade	No dopamine antagonist exposure; reflexes are increased, not decreased
Hypertensive crisis from tyramine reaction	Severe occipital headache, stiff neck, marked blood pressure surge; no clonus or diarrhea	Headache is mild and frontal; no neck stiffness; clonus and diarrhea point to serotonin toxicity
Discontinuation syndrome from fluoxetine	Dizziness, nausea, fatigue, irritability, sensory disturbances; no clonus or hyperthermia	Fluoxetine was stopped 4 weeks earlier; symptoms are acute and severe, not withdrawal-like

Watch out! The presence of inducible clonus is the single most useful bedside discriminator. Clonus is characteristic of serotonin toxicity and is not a feature of neuroleptic malignant syndrome or MAOI hypertensive crisis ^[3].
Key point! The headache in an MAOI tyramine reaction is typically severe and occipital, often described as the worst headache of life, and may be accompanied by neck stiffness. This patient’s mild frontal headache without neck stiffness makes hypertensive crisis unlikely.

Clinical Application
Serotonin syndrome is a clinical diagnosis based on exposure history and physical findings. The FAERS analysis confirms that serotonergic drug-drug interactions, including those involving SSRIs and other serotonergic agents, can produce serotonin syndrome as a potentially life-threatening adverse event . In this scenario, the patient was switched from fluoxetine to phenelzine, and the MAOI was already in effect when dextromethorphan was added. Any patient taking an MAOI must be counseled to avoid over-the-counter cough and cold products containing dextromethorphan because of the risk of rapid-onset serotonin toxicity. Management priorities include stopping the offending agents, supportive care, temperature control, and benzodiazepines for agitation and clonus; severe cases may require cyproheptadine or intensive care support ^[1][3].