A 28-year-old woman with major depressive disorder on sertraline 100 mg daily presents to the emergency department with a 6-hour history of agitation, confusion, and rapid speech. On examination, she is diaphoretic with a temperature of 39.2°C, blood pressure 158/94 mmHg, and heart rate 118/min. Her muscles are rigid, particularly in the lower limbs. She reports that her psychiatrist started her on phenelzine 30 mg daily 3 days ago for treatment-resistant depression. Deep tendon reflexes are brisk. What is the most likely diagnosis?

Explanation

## Clinical Diagnosis: Serotonin Syndrome ### Key Clinical Features Presented The patient presents with the classic triad of serotonin syndrome: 1. **Neuromuscular hyperactivity** — rigidity (especially lower limbs), brisk reflexes 2. **Autonomic instability** — fever (39.2°C), hypertension, tachycardia, diaphoresis 3. **Altered mental status** — agitation, confusion, rapid speech ### Temporal Relationship **Key Point:** The critical clue is the **recent addition of phenelzine (MAOI) to sertraline (SSRI)** 3 days ago. This combination is a classic serotonergic drug interaction that precipitates serotonin syndrome within hours to days. ### Diagnostic Criteria (Hunter Criteria) **High-Yield:** Serotonin syndrome diagnosis requires one of the following: - Spontaneous clonus (present as brisk reflexes/hyperreflexia in this case) - Inducible or ocular clonus + agitation or diaphoresis - Tremor + hyperreflexia - Hypertonia + temperature >38.5°C + ocular clonus or inducible clonus This patient meets multiple criteria. ### Pathophysiology **Clinical Pearl:** MAOIs prevent serotonin breakdown; SSRIs prevent reuptake. Combined, they cause excessive serotonergic activity at 5-HT~1A~, 5-HT~2A~, and 5-HT~7~ receptors in the CNS and periphery. ### Management 1. **Immediate:** Discontinue both agents 2. **Supportive care:** IV fluids, cooling measures for hyperthermia 3. **Pharmacologic:** Cyproheptadine (5-HT antagonist) 12 mg loading dose, then 2 mg every 2 hours or 4–8 mg every 6 hours 4. **Benzodiazepines:** For agitation and muscle rigidity ### Severity Grading | Severity | Features | |----------|----------| | **Mild** | Tremor, hyperreflexia, mydriasis, tachycardia | | **Moderate** | Clonus, rigidity, fever (38–39°C), agitation | | **Severe** | Severe rigidity, fever >40°C, rhabdomyolysis, DIC, altered consciousness | This patient has **moderate-to-severe** serotonin syndrome. ### Differential Exclusion - **NMS:** Requires antipsychotic exposure (absent here); slower onset (24–72 hrs); CK typically >1000 IU/L - **Anticholinergic toxicity:** Dry skin, dry mouth, urinary retention (not described) - **Thyroid storm:** No thyroid history; thyroid function tests would be abnormal [cite:Harrison 21e Ch 470]