A 28-year-old woman with major depressive disorder has been on sertraline 100 mg daily for 3 weeks. She visits a psychiatrist complaining of persistent low mood and is started on phenelzine 15 mg twice daily without washout. Within 36 hours, she develops severe agitation, tremor, hyperthermia (39.2°C), muscle rigidity, and hyperreflexia. Her creatine kinase is 2400 U/L and serum sodium is 128 mEq/L. What is the most likely diagnosis?

Explanation

## Clinical Presentation Analysis **Key Point:** Serotonin syndrome results from excessive serotonergic activity in the central nervous system, typically from combining serotonergic agents without adequate washout. ### Diagnostic Features Present This patient presents the classic **triad of serotonin syndrome**: 1. **Cognitive-behavioral changes**: Agitation, anxiety 2. **Autonomic instability**: Hyperthermia (39.2°C), tachycardia (implied) 3. **Neuromuscular hyperactivity**: Tremor, hyperreflexia, muscle rigidity ### Timeline & Mechanism The critical clue is the **rapid onset (36 hours)** following the addition of phenelzine (an MAOI) to ongoing sertraline (an SSRI). This combination dramatically increases synaptic serotonin through two mechanisms: - Sertraline blocks serotonin reuptake - Phenelzine inhibits monoamine oxidase, preventing serotonin degradation **High-Yield:** Serotonin syndrome onset is typically **within hours to 24 hours** of dose escalation or drug combination; NMS develops over **24–72 hours** and is associated with antipsychotics, not SSRIs + MAOIs. ### Supporting Laboratory Findings - **Elevated CK (2400 U/L)**: Reflects muscle hyperactivity and rhabdomyolysis risk - **Hyponatremia (128 mEq/L)**: SIADH from serotonergic overstimulation ### Hunter Criteria (Diagnostic Gold Standard) Patient meets **multiple criteria**: - Spontaneous clonus (hyperreflexia, tremor) - Inducible clonus (muscle rigidity) - Ocular clonus (not explicitly stated but tremor present) - Agitation + hyperthermia + hyperreflexia **Mnemonic: SEROTONIN SYNDROME = SOS** - **S**erotonergic drugs (SSRIs, MAOIs, tramadol, linezolid) - **O**nset rapid (hours to 24 hrs) - **S**igns: tremor, rigidity, hyperthermia, agitation, clonus ### Management Algorithm ```mermaid flowchart TD A[Suspected Serotonin Syndrome]:::outcome --> B{Hunter Criteria met?}:::decision B -->|Yes| C[Discontinue serotonergic agent]:::action C --> D[Supportive care + cooling]:::action D --> E{Severe/Refractory?}:::decision E -->|Yes| F[Cyproheptadine 12 mg load, then 2 mg Q4-6H]:::action E -->|No| G[Observation, monitor CK & Na]:::action F --> H[Most resolve within 24-72 hrs]:::outcome ``` **Clinical Pearl:** Cyproheptadine (a serotonin antagonist) is the specific antidote; it is NOT routinely given for mild cases but is essential in severe presentations with persistent hyperthermia or rhabdomyolysis risk. **Warning:** Do NOT confuse with NMS — NMS is triggered by **antipsychotics** (dopamine antagonists), develops more slowly, and presents with **lead-pipe rigidity** rather than hyperreflexia and clonus.