A 32-year-old woman on fluoxetine 40 mg daily for major depressive disorder is started on tramadol 50 mg for chronic back pain. She develops tremor, hyperreflexia, mydriasis, and agitation within 6 hours. Which of the following is NOT a feature of serotonin syndrome?

Explanation

## Serotonin Syndrome: Clinical Features and Pathophysiology **Key Point:** Serotonin syndrome results from excessive serotonergic activity in the CNS, typically from drug interactions (SSRIs + tramadol, MAOIs + SSRIs, linezolid + SSRIs). The classic triad is **altered mental status, autonomic instability, and neuromuscular abnormalities**. ### Characteristic Features (Hunter Criteria) | Feature Category | Clinical Manifestations | |---|---| | **Neuromuscular** | Tremor, hyperreflexia, clonus (spontaneous and inducible), muscle rigidity, myoclonus | | **Autonomic** | Hyperthermia (often marked), tachycardia, hypertension, diaphoresis, flushing | | **Mental Status** | Agitation, confusion, anxiety, restlessness, disorientation | | **GI** | Diarrhea, nausea, vomiting | **High-Yield:** Serotonin syndrome causes **hypertension and tachycardia**, NOT bradycardia and hypotension. This autonomic pattern distinguishes it from other drug toxidromes. ### Mechanism Excessive serotonin at postsynaptic 5-HT~1A~ and 5-HT~2A~ receptors in the brainstem and spinal cord → hyperexcitability of motor neurons and thermoregulatory centers. ### Common Drug Combinations That Trigger Serotonin Syndrome 1. SSRI + MAOI 2. SSRI + tramadol (as in this case) 3. SSRI + linezolid 4. SSRI + St. John's Wort 5. SSRI + metoclopramide (rare) 6. Serotonin agonists (buspirone, triptans) + SSRIs **Clinical Pearl:** The presence of **clonus** (especially inducible clonus on ankle dorsiflexion or patellar reflex) is highly specific for serotonin syndrome and helps differentiate it from neuroleptic malignant syndrome (NMS), where clonus is absent. ### Serotonin Syndrome vs. Neuroleptic Malignant Syndrome | Feature | Serotonin Syndrome | NMS | |---|---|---| | **Onset** | Hours to days | Days to weeks | | **Clonus** | Present (key feature) | Absent | | **Pupil size** | Mydriasis | Normal | | **GI symptoms** | Diarrhea (common) | Constipation | | **Trigger** | Serotonergic drugs | Antipsychotics | | **Hyperthermia** | Present | Present | | **Rigidity** | Present | Present (lead-pipe) | | **Autonomic** | Hypertension, tachycardia | Hypertension, tachycardia | **Warning:** Do NOT confuse serotonin syndrome with NMS — they are distinct entities with different triggers and slightly different clinical profiles. Clonus is the discriminator. ### Management 1. **Immediate:** Discontinue offending agent(s) 2. **Supportive care:** Cooling measures, IV fluids, benzodiazepines for agitation 3. **Severe cases:** Cyproheptadine (5-HT antagonist) 12 mg loading dose, then 2 mg every 2 hours or 4 mg every 6 hours 4. **ICU admission** if hyperthermia >39°C, severe rigidity, or rhabdomyolysis (check CK) **Tip:** In exam questions, always look for the autonomic sign that does NOT fit — serotonin syndrome = hypertension + tachycardia, NOT hypotension + bradycardia.