What over-the-counter (OTC) medication likely caused serotonin syndrome in a patient taking sertraline (selective serotonin reuptake inhibitor (SSRI)) with symptoms of altered mental status, diarrhea, abdominal cramps, tachycardia, hypertension, bilateral hyper-reflexia, and ankle clonus?

Dextromethorphan (Answer: D)

The patient most likely consumed dextromethorphan, an over-the-counter cough suppressant that, when combined with sertraline (an SSRI), precipitated serotonin syndrome. 1, 2, 3

Clinical Reasoning

This patient presents with the classic triad of serotonin syndrome:

• Mental status changes: altered sensorium 4, 2
• Neuromuscular hyperactivity: bilateral hyper-reflexia, ankle clonus 4, 2
• Autonomic instability: tachycardia (125/min), hypertension (170/100 mmHg), diarrhea, abdominal cramps 4, 2

The presence of clonus and hyperreflexia are highly diagnostic for serotonin syndrome and establish the diagnosis when occurring in the setting of serotonergic drug use. 4

Why Dextromethorphan is the Culprit

Dextromethorphan is a well-recognized serotonergic agent that significantly increases the risk of serotonin syndrome when combined with SSRIs like sertraline. 1, 2, 3

• The American Academy of Child and Adolescent Psychiatry specifically identifies dextromethorphan as a high-risk over-the-counter medication that should be avoided in patients taking sertraline due to increased serotonin syndrome risk. 1
• The FDA drug label for sertraline explicitly warns about serotonin syndrome with concomitant use of other serotonergic drugs, and dextromethorphan is specifically mentioned as a problematic agent. 2
• Published case reports with serum drug levels confirm that supra-therapeutic dextromethorphan doses combined with therapeutic SSRI levels are sufficient to cause serotonin syndrome. 3

Why Not the Other Options

Codeine (Option A): While opioids like tramadol and meperidine carry serotonin syndrome risk, codeine is not a significant serotonergic agent and would not typically cause this presentation. 1

Guaifenesin (Option B): This expectorant has no serotonergic activity and does not interact with SSRIs to cause serotonin syndrome. 1

Bromhexine (Option C): This mucolytic agent has no serotonergic properties and would not precipitate serotonin syndrome. 1

Critical Diagnostic Features

The 4-day timeline is consistent with serotonin syndrome, which typically develops within 24-48 hours after combining serotonergic medications or increasing doses. 1, 5

Myoclonus occurs in 57% of serotonin syndrome cases and is the most common clinical finding, making the presence of ankle clonus particularly diagnostic. 4

Common Clinical Pitfall

Failure to consider over-the-counter medications and supplements as potential contributors to serotonin syndrome is a frequent error in clinical practice. 1 Patients and providers often overlook that common cough suppressants containing dextromethorphan are potent serotonergic agents that can trigger life-threatening drug interactions. 1, 2

Management Priorities

Immediate treatment requires:

• Discontinuation of all serotonergic agents (both sertraline and dextromethorphan) 4, 2
• Benzodiazepines for agitation 4, 6
• Aggressive supportive care including IV fluids, management of vital sign abnormalities, and treatment of hyperthermia 4
• Cyproheptadine (serotonin antagonist) for severe cases 4, 7
• ICU admission with mechanical ventilation and paralysis if temperature exceeds 41.1°C 4

The mortality rate for serotonin syndrome is approximately 11%, with severe cases characterized by rhabdomyolysis, metabolic acidosis, renal failure, and disseminated intravascular coagulopathy. 4