A 32-year-old woman with major depressive disorder, treated with sertraline 100 mg daily for 3 months, presents to the emergency department with a 6-hour history of agitation, tremor, and muscle rigidity. Her husband reports she started taking her mother's tramadol (100 mg) for back pain yesterday. On examination: temperature 38.8°C, BP 145/92 mmHg, HR 118/min, generalized hyperreflexia, and clonus elicited at the ankles. Creatine kinase is 1200 U/L. What is the most likely diagnosis?

Explanation

## Clinical Presentation This patient presents with the classic triad of serotonin syndrome: **hyperthermia, neuromuscular hyperactivity (tremor, rigidity, hyperreflexia, clonus), and autonomic instability (tachycardia, hypertension, agitation)**. ### Key Diagnostic Features **Key Point:** Serotonin syndrome occurs when two or more serotonergic agents are combined, or when a single agent is given in excessive dose. The onset is typically **rapid (within 24 hours of dose increase or drug addition)**. In this case: - **Sertraline** (SSRI) — baseline serotonergic agent - **Tramadol** (opioid with SNRI properties and weak MAOI effect) — added yesterday - **Timeline:** Symptoms within 6 hours of tramadol addition → acute onset ### Hunter Criteria (Diagnostic Standard) The patient meets multiple criteria: 1. Clonus (spontaneous ankle clonus) — **most specific finding** 2. Hyperreflexia + tremor (neuromuscular signs) 3. Hyperthermia (38.8°C) 4. Agitation + tachycardia (autonomic signs) **High-Yield:** Clonus (especially inducible clonus) is the **single most sensitive and specific sign** of serotonin syndrome and distinguishes it from NMS. ### Severity Grading | Feature | Mild | Moderate | Severe | |---------|------|----------|--------| | Temperature | <38.5°C | 38.5–39.5°C | >39.5°C | | CK | Normal | 100–1000 U/L | >1000 U/L | | Clonus | Inducible | Spontaneous | Severe, sustained | | Consciousness | Alert | Agitated | Confused/altered | This patient is **moderate-to-severe** (CK 1200, fever 38.8°C, spontaneous clonus). ### Management Algorithm ```mermaid flowchart TD A[Suspected Serotonin Syndrome]:::outcome --> B[Discontinue all serotonergic agents]:::action B --> C{Severity?}:::decision C -->|Mild| D[Supportive care, observation]:::action C -->|Moderate| E[Benzodiazepines + IV fluids]:::action C -->|Severe| F[ICU admission, cyproheptadine]:::urgent E --> G[Monitor CK, urine myoglobin]:::action F --> H[Aggressive cooling, rhabdomyolysis prevention]:::action ``` **Clinical Pearl:** Unlike NMS (which develops over 24–72 hours and requires antipsychotic exposure), serotonin syndrome develops **acutely within hours** of drug combination and resolves within **24–48 hours** of discontinuation of serotonergic agents. **Mnemonic: SEROTONIN** — **S**peed of onset (hours), **E**xcitation (tremor, clonus), **R**igidity (mild-moderate), **O**ver-stimulation (agitation, hyperthermia), **T**achycardia, **O**ver-reflexia, **N**euromuscular hyperactivity, **I**nducible clonus, **N**eed to stop serotonergic drugs. ### Treatment 1. **Immediate:** Discontinue sertraline and tramadol 2. **Benzodiazepines:** Lorazepam 2–4 mg IV for agitation and muscle rigidity 3. **Cooling measures:** Passive cooling, IV fluids 4. **Monitor:** CK, urine myoglobin, renal function (rhabdomyolysis risk) 5. **Cyproheptadine:** Reserved for severe cases (5-HT1A/1B antagonist); 12 mg loading, then 2 mg every 2 hours × 3, then 4 mg every 6 hours [cite:Harrison 21e Ch 395]