A 32-year-old woman with major depressive disorder on sertraline 100 mg daily presents to the emergency department with a 6-hour history of agitation, tremor, and muscle rigidity. Her temperature is 38.5°C, blood pressure 145/92 mmHg, heart rate 112/min, and respiratory rate 24/min. On examination, she has hyperreflexia, clonus, and mydriasis. She reports starting fluoxetine 20 mg this morning as her psychiatrist switched her antidepressant without a washout period. Laboratory investigations show creatine kinase 1200 U/L and normal renal function. What is the most likely diagnosis?

Explanation

## Clinical Diagnosis: Serotonin Syndrome ### Presentation Pattern The patient presents with the classic triad of serotonin syndrome triggered by **serotonergic drug interaction**: 1. **Autonomic hyperactivity**: fever (38.5°C), tachycardia (112/min), hypertension, tachypnea 2. **Neuromuscular abnormalities**: tremor, muscle rigidity, hyperreflexia, clonus 3. **Altered mental status**: agitation ### Key Distinguishing Features **Key Point:** Serotonin syndrome develops **within hours** of serotonergic drug exposure or dose escalation, whereas NMS develops over **24–72 hours** after neuroleptic exposure. **High-Yield:** The temporal relationship is critical — this patient received fluoxetine *this morning* and symptoms appeared within 6 hours. This rapid onset rules out NMS. ### Mechanism of Serotonin Syndrome in This Case The patient was on sertraline (SSRI) and the psychiatrist added fluoxetine (another SSRI) without washout. Both drugs inhibit serotonin reuptake, causing excessive serotonergic activity in the CNS and periphery. ### Hunter Criteria (Diagnostic) **Mnemonic: HUNTER** — Hyperreflexia, Uncontrolled clonus, Neuromuscular rigidity, Temperature elevation, Excitement (agitation), Respiratory distress This patient meets multiple criteria: - Hyperreflexia ✓ - Clonus ✓ - Muscle rigidity ✓ - Fever ✓ - Agitation ✓ ### Serotonin Syndrome vs. Neuroleptic Malignant Syndrome | Feature | Serotonin Syndrome | NMS | |---------|-------------------|-----| | **Onset** | Hours to 24 hrs | 24–72 hrs | | **Trigger** | SSRI, MAOI, tramadol, linezolid, St. John's Wort | Antipsychotics (typical > atypical) | | **Clonus** | **Present** (especially ocular/inducible) | **Absent** | | **Hyperreflexia** | **Present** | Normal or decreased | | **GI symptoms** | Diarrhea common | Constipation common | | **CK elevation** | Mild to moderate | Marked (often >1000) | | **Prognosis** | Usually resolves in 24–72 hrs with drug cessation | Prolonged; may last weeks | **Clinical Pearl:** The presence of **clonus** (especially inducible clonus) is the single most specific finding for serotonin syndrome and is rarely seen in NMS. ### Management 1. **Immediate**: Stop all serotonergic agents 2. **Supportive care**: Cooling, IV fluids, benzodiazepines for agitation 3. **Specific agent**: Cyproheptadine (5-HT1A/1C antagonist) 12 mg loading, then 2 mg q2h (max 32 mg/day) 4. **Monitoring**: Serial CK, renal function, urine myoglobin **Warning:** Do NOT prescribe another SSRI or MAOI for at least 2 weeks after fluoxetine cessation (fluoxetine has a long half-life of 2–3 days and active metabolites). [cite:Harrison 21e Ch 395]