A 28-year-old woman with major depressive disorder has been on sertraline 100 mg daily for 3 weeks. She presents to the emergency department with a 6-hour history of agitation, tremor, hyperthermia (39.2°C), muscle rigidity, and hyperreflexia. Her husband reports she started taking over-the-counter cough syrup containing dextromethorphan yesterday for a cold. On examination, she is diaphoretic, has clonus in both lower limbs, and her creatine kinase is 1200 U/L. What is the most likely diagnosis?

Explanation

## Clinical Presentation This patient presents with the classic pentad of serotonin syndrome triggered by a drug–drug interaction. **Key Point:** Serotonin syndrome results from excessive serotonergic activity in the central nervous system, typically occurring within hours to days of starting a serotonergic agent or increasing its dose. ### Diagnostic Criteria (Hunter Criteria) The diagnosis requires one of the following in the setting of serotonergic drug use: 1. Spontaneous clonus 2. Inducible or ocular clonus + agitation or diaphoresis 3. Tremor + hyperreflexia 4. Hypertonia + temperature >38.5°C + ocular clonus or inducible clonus This patient meets multiple criteria: spontaneous clonus (lower limbs), agitation, diaphoresis, tremor, hyperreflexia, and hyperthermia. ### Mechanism Sertraline (SSRI) + dextromethorphan (weak SNRI/MAOI-like activity) → excessive serotonin accumulation in synapses. **High-Yield:** Dextromethorphan is a common OTC culprit; patients often do not recognize it as a drug interaction risk. ### Key Distinguishing Features | Feature | Serotonin Syndrome | NMS | |---------|-------------------|-----| | **Onset** | Hours to days | Days to weeks | | **Clonus** | Present (spontaneous/inducible) | Absent | | **Tremor** | Fine, prominent | Coarse, less prominent | | **GI symptoms** | Common (diarrhea) | Rare | | **Trigger** | Serotonergic drugs ± interactions | Antipsychotics (D2 blockade) | | **CK elevation** | Mild to moderate | Marked (often >1000) | | **Recovery** | Hours to days (drug half-life) | Days to weeks | **Clinical Pearl:** Clonus is the hallmark sign that distinguishes serotonin syndrome from NMS; it is almost never seen in NMS. ### Management 1. **Immediate:** Discontinue all serotonergic agents 2. **Supportive care:** IV fluids, cooling measures, benzodiazepines for agitation 3. **Severe cases:** Cyproheptadine (5-HT1A/1C antagonist) 12 mg loading dose, then 2 mg every 2 hours or 4 mg every 6 hours 4. **Monitor:** CK, renal function, electrolytes (risk of rhabdomyolysis) **Mnemonic — SEROTONIN (Signs of Serotonin Syndrome):** - **S**weating, Shivering - **E**xcitation, Euphoria - **R**igidity (hypertonicity) - **O**cular clonus - **T**remor - **O**scillations (clonus) - **N**ausea - **I**ncreased reflexes - **N**ew-onset hypertension **Warning:** Serotonin syndrome can progress rapidly to life-threatening complications (disseminated intravascular coagulation, acute kidney injury, hyperthermia-induced organ failure). Early recognition and drug discontinuation are critical.