In a patient on tranylcypromine who recently started dextromethorphan and now presents with confusion, sweating, anxiety, agitation, and tremor, which diagnosis is most likely: serotonin syndrome, discontinuation syndrome, hypertensive crisis, or dextromethorphan adverse effect?

Serotonin Syndrome

This patient has serotonin syndrome caused by the dangerous combination of tranylcypromine (an MAOI) and dextromethorphan. 1

Clinical Reasoning

The presentation is classic for serotonin syndrome with the characteristic triad:

• Mental status changes: confusion, anxiety, agitation 1, 2
• Autonomic hyperactivity: sweating (diaphoresis) 1, 2
• Neuromuscular abnormalities: tremor 1, 2

The timing is pathognomonic—symptoms developed within hours of starting dextromethorphan, which is the typical 6-24 hour window for serotonin syndrome onset after initiating or combining serotonergic agents. 1, 3

Why This Is Serotonin Syndrome and Not the Other Options

The drug combination is extremely high-risk. Tranylcypromine is a monoamine oxidase inhibitor (MAOI), and dextromethorphan is a well-established serotonergic agent that acts as a serotonin reuptake inhibitor at supratherapeutic doses. 1, 4, 5 The combination of an MAOI with any other serotonergic drug should be strictly avoided, as MAOIs are implicated in most severe presentations of serotonin syndrome. 1, 6

Discontinuation syndrome is ruled out because the patient is actively taking medications, not withdrawing from them. 1

Hypertensive crisis from MAOI-tyramine interactions presents differently—with severe headache, chest pain, and markedly elevated blood pressure as the primary features, not the neuromuscular hyperactivity (tremor) and mental status changes seen here. 1

Simple dextromethorphan adverse effect would not explain the constellation of symptoms. At therapeutic doses, dextromethorphan causes drowsiness or mild GI upset, not this acute syndrome with autonomic and neuromuscular features. 1, 5

Diagnostic Confirmation Using Hunter Criteria

The American Academy of Pediatrics recommends using the Hunter Criteria (sensitivity 84%, specificity 97%) for diagnosis. 1, 2 This patient meets criteria with:

• Serotonergic agent exposure (dextromethorphan + tranylcypromine) PLUS
• Tremor and likely hyperreflexia (though reflexes are pending, tremor in this context is highly suggestive) 1, 2

Key diagnostic features to assess immediately:

• Check for hyperreflexia and clonus (spontaneous, inducible, or ocular)—these are the most diagnostic neuromuscular signs, present in 57% of cases 1, 2
• Measure temperature (may be elevated up to 41°C in severe cases) 1
• Assess for myoclonus and muscle rigidity 1

Immediate Management Algorithm

Step 1: Discontinue ALL serotonergic agents immediately (both dextromethorphan and tranylcypromine). 1, 2, 3

Step 2: Initiate supportive care:

• IV fluids for autonomic instability 2, 3
• Benzodiazepines as first-line treatment for agitation, tremor, and neuromuscular symptoms 1, 2, 3
• External cooling measures (cooling blankets) if hyperthermia develops 2, 3
• Continuous cardiac monitoring 1, 2
• Avoid physical restraints—they worsen isometric muscle contractions, exacerbating hyperthermia and lactic acidosis 2, 3

Step 3: Assess severity and escalate if moderate-to-severe:

• For moderate-to-severe cases (significant hyperthermia, rigidity, severe agitation): Add cyproheptadine 12 mg orally initially, then 2 mg every 2 hours until symptom improvement, followed by maintenance of 8 mg every 6 hours 1, 2
• For intubated patients, crush tablets and administer via nasogastric tube (no parenteral formulation exists) 1

Step 4: Monitor for complications:

• Serial creatine kinase (CK ≥4× upper limit indicates rhabdomyolysis) 1
• Arterial blood gases (metabolic acidosis) 1
• Serum creatinine (renal failure) 1
• Liver transaminases 1
• Coagulation studies (disseminated intravascular coagulation) 1

Critical Pitfalls to Avoid

Antipyretics are ineffective for hyperthermia in serotonin syndrome because fever results from muscular hyperactivity, not hypothalamic dysregulation. 1, 2

Do not use indirect sympathomimetics (like dopamine) for blood pressure instability—use direct-acting agents (phenylephrine, norepinephrine) instead. 1

Avoid succinylcholine in severe cases due to risks of hyperkalemia and rhabdomyolysis. 1

Cyproheptadine may cause sedation and hypotension as side effects. 1, 2

Prognosis

The mortality rate for serotonin syndrome is approximately 11%, with about 25% of patients requiring intubation and ICU admission. 1, 2, 3 Most mild-to-moderate cases resolve within 24-48 hours after discontinuing serotonergic agents and initiating supportive care. 1