17.7 Psychiatric Emergencies: Severe Agitation, Serotonin Syndrome, NMS, Lithium Toxicity & Psychotropic Overdose
Key Takeaways
ACEP's 2023 severe agitation policy favors droperidol or an atypical antipsychotic combined with midazolam, and advises against midazolam alone when a single agent is used.
Serotonin syndrome develops within hours and features clonus and hyperreflexia; it is treated with benzodiazepines and cyproheptadine 12 mg, then 2 mg every 2 hours while symptoms continue.
Neuroleptic malignant syndrome develops over days with lead-pipe rigidity and slowed reflexes; it is treated by stopping the drug, cooling, benzodiazepines, and dantrolene or bromocriptine for severe cases.
EXTRIP recommends dialysis for lithium toxicity when the level exceeds 4.0 mEq/L with impaired kidney function, or with reduced consciousness, seizures or life-threatening dysrhythmias at any level.
Clozapine missed for 2 or more days must be restarted at 12.5 mg once or twice daily and re-titrated, even though FDA ended the clozapine REMS in 2025.
17.7 Psychiatric Emergencies: Severe Agitation, Serotonin Syndrome, NMS, Lithium Toxicity & Psychotropic Overdose
Note
Exam scope: 2025 outline subtopic 2B10 (Pharmacotherapy for Psychiatric Emergencies) with related toxicology from 2B13. Alcohol and sedative withdrawal are covered in Section 8.4, and tricyclic and anticholinergic toxicity in Section 9.1.
Severe Agitation
Medical Causes First
Agitation is a symptom, not a diagnosis. Check glucose, oxygenation and vital signs early and consider hypoglycemia, hypoxia, intoxication, withdrawal, CNS infection, head injury, thyroid storm and delirium. ACEP no longer recognizes the term "excited delirium"; describe the presentation clinically instead, such as hyperactive delirium with severe agitation.
Verbal de-escalation comes first. Offer oral medication to a patient who will cooperate:
- Olanzapine orally disintegrating tablets 10 mg
- Risperidone 2 mg (liquid or orally disintegrating)
- Lorazepam 2 mg
- Sublingual dexmedetomidine film (approved in 2022 for agitation in schizophrenia or bipolar disorder)
Parenteral Treatment (ACEP Clinical Policy, 2023)
| Strength | Recommendation |
|---|---|
| Level B | For faster and more effective control, use droperidol plus midazolam or an atypical antipsychotic plus midazolam |
| Level B | If only one drug can be given, use droperidol or an atypical antipsychotic rather than midazolam alone, because midazolam alone has more adverse effects |
| Level B | Haloperidol alone, or with lorazepam, is also effective |
| Level C (consensus) | When the safety of the patient, bystanders or staff is threatened, consider ketamine IV or IM |
| Drug | Typical adult IM dose | Notes |
|---|---|---|
| Droperidol | 5 mg (2.5 to 10 mg) | Boxed warning for QT prolongation (2001); ED studies show dysrhythmias are rare at these doses |
| Haloperidol | 5 mg, often with lorazepam 2 mg | Dystonia (prevented or treated with diphenhydramine or benztropine), QT prolongation |
| Olanzapine | 10 mg | Do not combine IM olanzapine with parenteral benzodiazepines, because of reports of fatal cardiorespiratory depression |
| Ziprasidone | 10 to 20 mg (maximum 40 mg/day) | QT prolongation; slower onset |
| Midazolam | 5 mg | Fast IM onset; respiratory depression, especially with alcohol |
| Ketamine | 4 to 5 mg/kg | Fastest control; vomiting, laryngospasm, emergence reactions, and higher intubation rates in some prehospital series |
Monitor every chemically restrained patient continuously, with capnography when deeply sedated. Avoid prone restraint, which has been linked to deaths, and remove restraints as soon as possible.
Drug-Induced Hyperthermic Syndromes
| Feature | Serotonin syndrome | Neuroleptic malignant syndrome (NMS) | Anticholinergic toxicity | Malignant hyperthermia |
|---|---|---|---|---|
| Trigger | Serotonergic drugs, often a new agent or dose increase | Dopamine antagonists, or stopping dopaminergic drugs | Antimuscarinic drugs | Volatile anesthetics, succinylcholine |
| Onset | Hours (usually within 24) | Days to weeks | Hours | Minutes to hours during anesthesia |
| Neuromuscular | Clonus and hyperreflexia, legs more than arms | Lead-pipe rigidity, slowed reflexes | Normal | Rigidity |
| Skin | Diaphoretic | Diaphoretic | Dry | Mottled, diaphoretic |
| Pupils | Dilated | Normal | Dilated | Normal |
| Bowel sounds | Increased, diarrhea | Normal or decreased | Absent | Normal |
| Key treatment | Benzodiazepines, cyproheptadine | Stop the drug, cooling, benzodiazepines, dantrolene or bromocriptine | Physostigmine in selected patients (Section 9.1) | Dantrolene 2.5 mg/kg IV |
Serotonin Syndrome
Hunter criteria (in a patient taking a serotonergic drug), any one of:
- Spontaneous clonus
- Inducible clonus with agitation or diaphoresis
- Ocular clonus with agitation or diaphoresis
- Tremor with hyperreflexia
- Hypertonia with temperature above 38 °C and ocular or inducible clonus
Common culprits: SSRIs, SNRIs and MAO inhibitors combined with linezolid, methylene blue, tramadol, meperidine, fentanyl, dextromethorphan, triptans (low risk) or MDMA.
Treatment:
- Stop all serotonergic drugs and give supportive care.
- Give benzodiazepines for agitation and muscle activity.
- Give cyproheptadine 12 mg orally or by tube, then 2 mg every 2 hours while symptoms continue. Maintenance is 8 mg every 6 hours (maximum 32 mg/day). It is available only orally and sedates.
- For temperature above about 41 °C, give sedation, non-depolarizing paralysis and intubation. Antipyretics do not work because the heat comes from muscle activity.
- Avoid physical restraints, which increase muscle activity and lactic acidosis.
Neuroleptic Malignant Syndrome
- Stop the antipsychotic (or restart a dopaminergic drug that was stopped abruptly, such as levodopa).
- Cool actively, give IV fluids for rhabdomyolysis, and give benzodiazepines.
- For severe or progressive cases:
- Dantrolene 1 to 2.5 mg/kg IV, repeated as needed (up to about 10 mg/kg/day) to relax muscle.
- Bromocriptine 2.5 mg by mouth or tube every 8 hours, titrated, to restore dopamine activity.
- Amantadine is an alternative, and electroconvulsive therapy is used for refractory cases.
- Wait at least 2 weeks after recovery before carefully restarting an antipsychotic, using a lower-potency agent at a low dose.
Lithium Toxicity
The therapeutic range is about 0.6 to 1.2 mEq/L. Lithium is cleared by the kidneys and handled like sodium.
| Type | Features |
|---|---|
| Acute (no prior use) | GI symptoms first; neurotoxicity appears later as lithium enters the brain; a high level can be fairly well tolerated at first |
| Chronic (dehydration, kidney injury, interacting drugs) | Neurotoxicity at modestly raised levels: tremor, confusion, hyperreflexia, ataxia, seizures |
| Acute-on-chronic | Both, often severe |
Precipitants of chronic toxicity: volume depletion, NSAIDs, ACE inhibitors and ARBs, thiazide diuretics, and kidney injury.
Treatment:
- IV normal saline to restore volume and lithium clearance. Watch sodium, because lithium-induced nephrogenic diabetes insipidus can cause hypernatremia.
- No activated charcoal, which does not bind lithium. Use whole bowel irrigation for large sustained-release ingestions (Section 8.1).
- Stop interacting drugs.
- Hemodialysis (EXTRIP 2015):
- Recommended when the level is above 4.0 mEq/L with impaired kidney function, or with decreased consciousness, seizures or life-threatening dysrhythmias at any level.
- Suggested when the level is above 5.0 mEq/L, there is significant confusion, or the expected time to reach a level below 1.0 mEq/L with optimal care is more than 36 hours.
- Recheck the level after dialysis, because lithium redistributes from tissue and levels rebound.
Some patients have lasting cerebellar damage (the syndrome of irreversible lithium-effectuated neurotoxicity, SILENT).
Dangerous Features of Psychotropic Overdoses
| Agent | Key toxicity | Pharmacist pearl |
|---|---|---|
| Bupropion | Seizures (can be delayed with extended-release forms), tachycardia, QRS widening | Observe extended-release ingestions for at least 24 hours |
| Venlafaxine | Seizures, sodium-channel cardiotoxicity, serotonin toxicity | More toxic in overdose than SSRIs |
| Citalopram, escitalopram | QTc prolongation that can be delayed for hours, seizures | Use serial ECGs |
| Quetiapine | Sedation, hypotension (alpha blockade), tachycardia | Often intubated for airway protection |
| Tricyclic antidepressants | Sodium-channel block, seizures, anticholinergic effects | Sodium bicarbonate for QRS of 100 ms or more (Section 9.1) |
| MAO inhibitors | Delayed hypertensive crisis followed by hypotension; serotonin syndrome | Admit for at least 24 hours of monitoring |
Patients Boarding With Psychiatric Illness
- Continue home psychiatric medications. Omissions cause withdrawal, relapse and longer stays. Confirm doses with the pharmacy or clinic, and record when long-acting injectable antipsychotics are due.
- Clozapine:
- If 2 or more days have been missed, restart at 12.5 mg once or twice daily and re-titrate. Restarting at the full dose risks hypotension, bradycardia, syncope and seizures.
- Clozapine also causes constipation and ileus, myocarditis, seizures and neutropenia.
- Stopping smoking raises clozapine levels, because tobacco smoke induces CYP1A2. This matters in smoke-free EDs.
- FDA ended the clozapine REMS program in 2025, but it still recommends monitoring the absolute neutrophil count as described in the labeling.
- Suicide risk: screen with a validated tool. At discharge, limit the quantity of dangerous medications and counsel on restricting access to lethal means, including stored medications and firearms. The Joint Commission's 2026 National Performance Goals include a goal on reducing suicide risk.
A 30-year-old man is severely agitated and violent, threatening staff after methamphetamine use, and verbal de-escalation has failed. He has no IV access. Glucose is 112 mg/dL. Under ACEP's 2023 clinical policy, which IM regimen best balances rapid control and safety?
Midazolam 5 mg IM given alone, repeated every 10 minutes
Diphenhydramine 50 mg IM given alone
Olanzapine 10 mg IM plus lorazepam 2 mg IM together
Droperidol 5 mg IM plus midazolam 5 mg IM
A 52-year-old woman taking sertraline 150 mg daily started linezolid for MRSA pneumonia yesterday. She now has agitation, diaphoresis, diarrhea, a temperature of 38.6 °C, and inducible ankle clonus, more marked in the legs. What is the most appropriate pharmacologic plan, together with stopping the serotonergic drugs?
Haloperidol 5 mg IM for agitation
Bromocriptine 2.5 mg every 8 hours
Physostigmine 1 mg IV over 5 minutes
Benzodiazepines plus cyproheptadine 12 mg
A 66-year-old on long-term lithium had a week of vomiting and diarrhea and took ibuprofen daily for back pain. She is confused and tremulous and had a generalized seizure in the ED. Lithium is 3.1 mEq/L and creatinine 2.6 mg/dL (baseline 1.0). Besides IV normal saline, what is most appropriate?
Emergent hemodialysis
Activated charcoal 1 g/kg, repeated every 4 hours
Sodium bicarbonate infusion to alkalinize the urine
Whole bowel irrigation until the effluent is clear
A 34-year-old man with schizophrenia who has taken clozapine 400 mg daily for years has been boarding in the ED for 4 days without receiving it. The team wants to restart his home dose tonight. What is the most appropriate recommendation?
Restart at 400 mg tonight, because he tolerated it for years
Do not restart until an ANC is reported through the REMS program
Restart at 12.5 mg once or twice daily and re-titrate
Give 200 mg tonight and 400 mg daily from tomorrow
Sections you finish are checked off in the contents.