Psychiatry Toolkit (PsychToolkit)

Serotonin toxicity

Serotonin toxicity is a dose-related spectrum of excess CNS serotonin, not an idiosyncratic reaction. It starts within hours of a dose change or new combination. Diagnose with the Hunter criteria, stop the serotonergic drugs, and treat severe cases (temperature >39 °C or rapidly rising, rigidity with sustained clonus) as a medical emergency.

Definition and terminology

• "Serotonin toxicity" is preferred to "serotonin syndrome", because it is a spectrum from mild to life-threatening.
• It occurs in three settings: adverse reaction at therapeutic doses (usually mild to moderate), overdose of one agent (usually moderate), and drug interactions (almost all severe cases).
• Serotonin toxicity occurs in about 15% of SSRI overdoses, but single-agent SSRI overdose rarely causes severe toxicity.
• Severe toxicity almost always comes from combining drugs that act at different sites, most commonly an MAOI plus a serotonin reuptake inhibitor.

Causes

Methylene blue is a potent MAO-A inhibitor. Combining it with an SSRI, SNRI or TCA can cause severe toxicity (relevant in surgery, sepsis and vasoplegia).

Pathophysiology

Excess serotonin in the CNS overstimulates postsynaptic receptors. The life-threatening effects (rigidity, hyperthermia) are mediated mainly by 5-HT2A receptors, which is the basis for using 5-HT2A antagonists.

Clinical features

Diagnosis: Hunter Serotonin Toxicity Criteria

In a patient who has taken a serotonergic agent, ANY ONE of:

1. Spontaneous clonus.
2. Inducible clonus AND (agitation OR diaphoresis).
3. Ocular clonus AND (agitation OR diaphoresis).
4. Tremor AND hyperreflexia.
5. Hypertonia AND temperature >38 °C AND (ocular OR inducible clonus).

The Hunter criteria (sensitivity 84%, specificity 97%) were developed at the Hunter Area Toxicology Service in Newcastle, NSW. They are more specific than Sternbach's criteria, whose features overlap with anticholinergic delirium, withdrawal states and SSRI discontinuation. The key bedside step is a focused neurological exam: tone, reflexes, clonus (including ocular) and pupils.

Severity

• Mild: tremor, mild tachycardia, inducible clonus, lower-limb hyperreflexia. Often occurs at therapeutic doses and rarely troubles the patient.
• Moderate: agitation, sustained clonus, tachycardia, temperature <39 °C. Distressing; needs symptomatic relief.
• Severe (serotonergic crisis): rapidly progressive hyperthermia, rigidity with sustained clonus, seizures. Progresses to multi-organ failure within hours if untreated. An MAOI or stimulant is often involved.

Delirium is not prominent, which helps separate it from anticholinergic toxicity. Symptoms usually resolve within 12–24 hours of stopping the drugs.

Differential diagnosis

The key distinguishing sign is neuromuscular excitation (hyperreflexia, clonus, myoclonus). It is absent in NMS, anticholinergic delirium, CNS infection and malignant hyperthermia. Sympathomimetic toxicity can share hyperreflexia and tremor, but lacks sustained clonus. eTG also lists withdrawal syndromes (alcohol, baclofen, benzodiazepines, GHB) and non-convulsive seizures as mimics. See the Comparison table.

Investigations

• Mild: UEC, CK, glucose, venous blood gas, ECG.
• Moderate to severe: add FBC, LFTs, calcium, coagulation.
• In overdose: paracetamol level, ECG for QTc (e.g. citalopram, escitalopram) and QRS (TCAs).

Management

1. Stop all serotonergic drugs.
2. Observe: at least 6 hours for moderate toxicity; 12 hours after slow-release preparations such as venlafaxine XR.
3. Mild: supportive care only.
4. Moderate, distressed: oral diazepam first. If no improvement, add cyproheptadine (oral 5-HT2A antagonist). No controlled trials, but used successfully in practice.
5. Moderate, cannot take oral: IV diazepam or midazolam. IV chlorpromazine is an alternative, but causes postural hypotension and can be fatal if the diagnosis is actually NMS.
6. Severe: urgent clinical toxicologist advice and ICU. Rapid cooling for rising temperature, with cold IV fluids first-line (patients are usually volume depleted). Sedate for rigidity and sustained clonus; intubation, ventilation and paralysis may be needed. Treat seizures as for poisoning.
7. Avoid: antipyretics (no effect), dantrolene (no evidence), bromocriptine (may worsen toxicity), and physical restraint (increases heat and lactic acidosis).

eTG dosing (adults):

Benzodiazepine-tolerant patients may need higher doses. Paediatric doses are in eTG.

Complications

Rhabdomyolysis, acute kidney injury, metabolic acidosis, hyperkalaemia, liver failure, DIC, seizures, death.

Restarting and prevention

• Most patients recover fully within 24–72 hours. Reintroduce serotonergic treatment only after resolution, ideally one agent at a time at a lower dose.
• Avoid MAOI combinations. Isbister et al. suggest this alone would prevent most life-threatening toxicity.
• Respect washout periods when switching to or from an MAOI (fluoxetine has a long half-life); use Psymatik for switching schedules. Tyramine restrictions continue for 14 days after stopping phenelzine or tranylcypromine (see MAOI).
• Watch for non-psychiatric serotonergic drugs: tramadol, fentanyl, pethidine, dextromethorphan, linezolid, methylene blue, triptans (low risk).
• Report to the TGA.

Sources

• eTG Toxicology and Toxinology: Serotonergic toxidrome (published August 2020; accessed 8 Oct 2026).
• Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust 2007;187(6):361–5.
• Dunkley EJC et al. The Hunter Serotonin Toxicity Criteria. QJM 2003;96:635–42.
• Isbister GK, Buckley NA. The pathophysiology of serotonin toxicity. Clin Neuropharmacol 2005.
• NHS GGC. Serotonin toxicity management, paediatrics (dantrolene and antipyretics).

Lithium toxicity

Lithium has a narrow therapeutic index and is cleared almost entirely by the kidneys, so anything that lowers kidney function can tip a stable patient into toxicity. Chronic toxicity is the most common and most dangerous pattern, and can be severe at only modestly raised levels. Treat the patient, not the number.

Pharmacology relevant to toxicity

• Lithium behaves like sodium: distributed through total body water, not protein-bound, and eliminated by the kidneys.
• Usual half-life is about 12 hours, and much longer in renal impairment.
• Lithium moves into and out of the CNS slowly. Acute overdose can look well despite a high level, chronic toxicity causes neurotoxicity at lower levels, and neurological recovery lags behind the fall in serum level (days to weeks).
• eTG lists 0.5–1.0 mmol/L as therapeutic. The ISBD/IGSLI consensus maintenance target is 0.6–0.8 mmol/L (0.4–0.6 if good response but poor tolerance, or in older adults; 0.8–1.0 if insufficient response and well tolerated).

Patterns of toxicity

Precipitants of chronic toxicity

• Volume loss: vomiting, diarrhoea, fever, poor intake, heat, low-salt diet.
• Reduced kidney function: AKI, CKD, nephrogenic diabetes insipidus (common on long-term lithium) with inability to drink enough.
• Drugs: ACE inhibitors, angiotensin receptor blockers, NSAIDs, thiazide and loop diuretics; any recent dose increase or new medicine.
• Patient factors (eTG): age over 50, previous lithium toxicity, intercurrent illness, thyroid dysfunction.

Clinical features

eTG's guide for chronic accumulation is below. Interpret the level alongside the clinical picture and time since last dose.

• Cardiac: bradycardia and hypotension; QT prolongation is uncommon and arrhythmias are rare.
• Renal: nephrogenic DI causes polyuria (obligatory water loss 3–12 L/day), dehydration and hypernatraemia, which in turn worsen toxicity.
• Lithium can contribute to serotonin toxicity when combined with serotonergic drugs.

SILENT

The syndrome of irreversible lithium-effectuated neurotoxicity: lasting neurological damage after lithium toxicity, mainly cerebellar (ataxia, dysarthria, nystagmus), sometimes with cognitive impairment or movement disorders. Recovery from neurotoxicity may take weeks and can be incomplete, so early treatment matters.

Investigations

• Serum lithium: in acute or acute-on-chronic poisoning, every 6 hours to find the peak and confirm elimination (serum levels do not reflect CNS or total body load). In chronic toxicity, repeat until clearly falling. Note the time of the last dose.
• Creatinine and urea.
• Serum sodium: every 6–12 hours if conscious state is altered, to assess hydration and detect hypernatraemia.
• TFTs (chronic toxicity).
• ECG.
• Calcium, glucose, venous blood gas. In overdose: paracetamol level and co-ingestant screen.
• Nephrogenic DI clues: thirst and drinking >5 L/day, polyuria and nocturia, sodium at the upper end of normal, urine osmolality low relative to serum.

Management

1. Stop lithium and all nephrotoxic or interacting drugs (ACE inhibitors, ARBs, NSAIDs, diuretics).
2. Escalate: NSW Poisons Information Centre 13 11 26 or a clinical toxicologist; nephrology early if haemodialysis may be needed.
3. Airway: manage urgently if reduced consciousness compromises airway or breathing.
4. Fluids: IV sodium chloride 0.9% is first-line for dehydration and enhances lithium elimination when kidneys work. Patients with nephrogenic DI need larger-than-usual volumes to match high urine output. Watch sodium closely.
5. Seizures: check sodium and treat nephrogenic DI. Self-limiting seizures need no treatment; persistent or recurrent seizures get an IV benzodiazepine.
6. Decontamination (acute ingestion): activated charcoal is not recommended (it does not bind lithium). For ingestions >50 g, consider whole bowel irrigation within 4 hours, with a clinical toxicologist. The patient must protect their airway or be intubated; do not use if aspiration risk or ileus; check hourly for distension.
7. Haemodialysis: see below.
8. Disposition, acute: admit if haemodialysis or treatment of neurotoxicity is needed. Discharge if asymptomatic after 6–12 hours of observation with serial levels <1.5 mmol/L and falling.
9. Disposition, chronic: admit if there is neurotoxicity (e.g. coma, seizures). Lithium does not need restarting immediately; consider stopping or reducing the dose, as recurrence risk is high.
10. Advise no driving or operating machinery for at least 3 days after discharge (chronic toxicity).

Haemodialysis criteria (EXTRIP 2015)

eTG, acute and acute-on-chronic: haemodialysis is rarely needed with normal kidney function and only after discussion with a clinical toxicologist. Consider it for severe toxicity (especially neurotoxicity such as coma or seizures), lithium >4.0 mmol/L with kidney impairment, or lithium >5.0 mmol/L. Continue until clinical improvement and level <1.0 mmol/L, or at least 6 hours if levels are not readily available.

eTG, chronic: not usually needed if kidney function is normal. Indicated if the level is expected to still be >1.0 mmol/L at 36 hours, or there are features of severe toxicity. eTG uses a nomogram (Buckley et al. 2020) plotting eGFR against the presenting level to predict the 36-hour level; discuss with a clinical toxicologist. Even low-intensity CRRT at least doubles lithium clearance.

In all cases, monitor the level after dialysis for rebound.

Prevention

Most chronic toxicity is preventable with routine monitoring and a sick-day plan. RANZCP 2020 refers clinicians to the Lithiumeter (Malhi et al. 2016) for prescribing and monitoring.

Monitor more often with intercurrent illness, interacting drugs, older age, renal impairment or any sign of toxicity.

• Sick-day plan: written instructions to withhold lithium and seek review with vomiting, diarrhoea, fever, poor intake, new coarse tremor, unsteadiness or confusion; check level and kidney function during any intercurrent illness.
• Interactions: ACE inhibitors, ARBs, NSAIDs and thiazides can raise levels up to fourfold; tell other prescribers and pharmacists. Carbamazepine can cause neurotoxicity without a rise in level.
• Older adults: use greater caution; cognitive worsening can occur even at low levels (RANZCP 2020).
• Pregnancy (RANZCP 2020): if continuing lithium, reduce to 500 mg/day in the first trimester; divided doses with a trough of about 0.6 mmol/L in the second and third trimesters; monitor levels regularly as fluid volume changes; reduce 2 weeks before delivery and reintroduce soon after. Breastfeeding on lithium is not recommended. Offer foetal echocardiography and level-2 ultrasound.

Sources

• eTG Toxicology and Toxinology: Acute lithium poisoning; Chronic lithium accumulation (published August 2020, chronic amended December 2024; accessed 8 Oct 2026).
• Buckley NA et al. Haemodialysis for lithium poisoning: translating EXTRIP recommendations into practical guidelines. Br J Clin Pharmacol 2020;86(5):999–1006 (cited in eTG).
• Malhi GS et al. The 2020 RANZCP clinical practice guidelines for mood disorders. Aust N Z J Psychiatry 2021;55(1):7–117.
• Psych Scene Hub. Lithium prescribing and monitoring in clinical practice (updated June 2026), citing Nolen et al. 2019 (ISBD/IGSLI) and Gitlin 2016.
• Reimann F, Whyte I. Chronic lithium toxicity. Aust Prescr 2022;45:93–4.
• Decker BS et al. EXTRIP recommendations for lithium poisoning. Clin J Am Soc Nephrol 2015;10:875–87.
• WA Country Health Service. Specialised medication: lithium guideline (interactions).
• CMAJ. Lithium toxicity, 2021 (patterns of toxicity).

Anticholinergic toxicity

Anticholinergic toxicity is an agitated delirium with hot, dry skin, dilated pupils, tachycardia and urinary retention. The priority is controlling the delirium: physostigmine for severe cases from a pure anticholinergic, otherwise sedation with a benzodiazepine or droperidol.

Causes

In psychiatric settings, think of cumulative anticholinergic burden in older adults (e.g. benzatropine plus a TCA plus an antipsychotic), not only overdose.

Pathophysiology

Competitive blockade of muscarinic acetylcholine receptors. Peripheral blockade causes the autonomic signs; central blockade causes delirium.

Clinical features

Mnemonic: hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter, full as a flask.

Differential diagnosis

Dry skin and absent bowel sounds separate it from serotonin and sympathomimetic toxicity (both sweaty). Normal tone and no clonus separate it from NMS and serotonin toxicity. Also consider CNS infection, alcohol or sedative withdrawal, and other causes of delirium.

Investigations

• ECG: QRS and QTc, especially if a TCA or antihistamine may be involved.
• Bladder scan for retention.
• UEC, CK, glucose, venous blood gas; paracetamol level in overdose.
• Exclude other causes of delirium as clinically indicated.

Management

1. Supportive care in a low-stimulus environment with close observation. Mild cases may need observation only.
2. Catheterise acute urinary retention. This can settle agitation and avoid sedation.
3. Mild to moderate, cooperative: oral diazepam.
4. Severe, pure anticholinergic: physostigmine is the first-line antidote. It reverses delirium (which also helps confirm the diagnosis) and allows later sedation to be oral. Give in a resuscitation area. Avoid in bradycardia or bronchospasm. Short-acting, so repeat doses are often needed after 1–2 hours.
5. Mixed agents (TCA, antihistamine): consult a clinical toxicologist before physostigmine, because seizures and arrhythmias have been reported.
6. If physostigmine is unavailable: parenteral sedation with droperidol or a benzodiazepine. Large IV doses may be needed. Droperidol is contraindicated if the cause is antipsychotic toxicity or NMS is possible.
7. Restraint: avoid if possible; only briefly and alongside sedation.

Physostigmine is not registered in Australia. It is available through the Special Access Scheme; check your state's emergency and life-saving drugs register for hospitals that hold stock.

eTG dosing (adults):

Paediatric doses are in eTG.

TCA overdose (summary)

TCAs cause anticholinergic toxicity plus sodium-channel blockade, which drives the deaths. Physostigmine is risky in TCA poisoning. See TCA poisoning.

Sources

• eTG Toxicology and Toxinology: Anticholinergic toxidrome (published August 2020; accessed 8 Oct 2026).
• Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium. Br J Clin Pharmacol 2016;81(3):516–24 (cited in eTG).

TCA poisoning

TCA overdose kills through sodium-channel blockade, coma and seizures, and deteriorates fast: effects appear within 2 hours and most serious complications occur within 6. Call a clinical toxicologist or NSW Poisons Information Centre 13 11 26 early. Key treatments are early intubation, activated charcoal and serum alkalinisation with sodium bicarbonate.

Drugs

Amitriptyline, clomipramine, dosulepin, doxepin, imipramine, nortriptyline.

Risk assessment by dose

Asymptomatic at 6 hours means toxicity is unlikely. Acidosis (from respiratory depression, seizures or reduced consciousness) worsens all effects.

Clinical features

• CNS: rapidly falling consciousness, respiratory depression, coma; seizures in severe poisoning (linked to QRS widening).
• Cardiovascular: hypotension (alpha blockade, myocardial depression), sinus tachycardia, QRS widening and arrhythmias.
• Anticholinergic: mydriasis, warm dry skin, dry mouth, urinary retention, reduced bowel sounds. Anticholinergic delirium can persist 24–48 hours after recovery and becomes more obvious as sedation wears off.

ECG changes

• Sinus tachycardia.
• QRS widening: the wider the QRS, the higher the risk of ventricular arrhythmias and seizures.
• Dominant R wave in aVR (>3 mm, R:S ratio about 2:1): sensitive predictor of arrhythmias and seizures.
• Broad-complex tachycardia, with P waves lost in the preceding T wave.
• QT prolongation accompanies QRS widening but is not clinically significant; torsades is not usually seen.

Investigations

• ECG on arrival and serially: continuous monitoring and 12-lead ECGs every 2 hours for at least 6 hours if conscious state is altered.
• Blood gas to monitor acidosis and alkalinisation.
• Serum potassium during alkalinisation (bicarbonate causes hypokalaemia).
• Paracetamol level and co-ingestant screen.

Management

1. Escalate early: clinical toxicologist or 13 11 26; ICU for severe poisoning.
2. Intubate and ventilate if ingestion >20 mg/kg, or there is falling consciousness, seizures, hypotension or progressive ECG changes. Ideally within 2 hours of ingestion. Hand-ventilate during induction to avoid apnoea and worsening acidosis; consider a dose of sodium bicarbonate at induction.
3. Activated charcoal for ingestions >5 mg/kg if alert, cooperative, able to protect airway and within 2 hours; any time via NG or OG tube if intubated.
4. Serum alkalinisation if QRS widening is progressive with airway, breathing or circulatory compromise (arrhythmias, hypotension) or CNS depression: IV sodium bicarbonate plus hyperventilation, targeting pH 7.45–7.55. Bicarbonate is also the antiarrhythmic of choice.
5. Hypotension: IV fluids first; noradrenaline if persistent.
6. Seizures: usually brief and self-limiting but signal severe toxicity. Persistent or recurrent seizures: IV benzodiazepine and intubation.
7. Avoid class 1A antiarrhythmics (quinidine, procainamide). Follow ALS protocols for arrest, with toxicologist advice.
8. Disposition: admit if symptomatic; discharge if asymptomatic for at least 6 hours. Advise no driving or operating machinery for at least 3 days.

eTG dosing (adults and children):

Replace potassium to normal during alkalinisation.

Psychiatric relevance

TCAs are still prescribed for depression, pain and insomnia. When prescribing to someone at risk of suicide, consider the quantity dispensed and safer alternatives.

Sources

• eTG Toxicology and Toxinology: Tricyclic antidepressant (TCA) poisoning (published August 2020, amended September 2025; accessed 8 Oct 2026).
• Bailey B, Buckley NA, Amre DK. Prognostic indicators after TCA overdose: meta-analysis. J Toxicol Clin Toxicol 2004;42(6):877–88 (cited in eTG).
• Liebelt EL et al. Lead aVR versus QRS interval in predicting seizures and arrhythmias in TCA toxicity. Ann Emerg Med 1995;26(2):195–201 (cited in eTG).

Sympathomimetic toxicity

Sympathomimetic toxicity is adrenergic excess: agitation, tachycardia, hypertension, hyperthermia and sweating. Benzodiazepines are the cornerstone, treating agitation, tachycardia, hypertension and seizures together. In psychiatry it presents as stimulant-related agitation or psychosis, or as toxicity from ADHD medicines, MAOIs or SNRIs.

Causes

The picture varies with each drug's balance of adrenergic, dopaminergic and serotonergic effects.

Clinical features

Differential diagnosis

Serotonin toxicity (sustained clonus, often a serotonergic co-ingestant), anticholinergic toxicity (dry skin, absent bowel sounds), alcohol or sedative withdrawal, thyroid storm, CNS infection, primary psychosis or mania. Remember the medical complications that can present as agitation: stroke, intracranial haemorrhage, dissection.

Investigations

• ECG and troponin if chest pain or ECG changes.
• UEC, potassium, glucose, CK, venous blood gas (lactate).
• CT brain if focal signs, severe headache or reduced consciousness.
• Paracetamol level if overdose is possible.

Management

1. Sedation: IV benzodiazepines for severe agitation, also treating tachycardia and hypertension. Large doses are often needed. Oral diazepam may be enough for a cooperative, mildly agitated patient.
2. If benzodiazepines fail in severe agitation with signs of excited delirium: droperidol.
3. Hyperthermia (>39 °C or rapidly rising): rapid cooling urgently; cold IV fluids first-line (patients are usually volume depleted).
4. Persistent hypertension despite sedation: IV glyceryl trinitrate. If maximum rate is reached, ask a clinical toxicologist about other agents (e.g. beta blockers).
5. Seizures: IV benzodiazepines at larger doses than for sedation. Other anticonvulsants are often ineffective.
6. Complications: manage ACS, dissection, stroke, arrhythmias and rhabdomyolysis on their own pathways.

eTG dosing (adults):

Benzodiazepine-tolerant patients may need more. Paediatric doses are in eTG.

Stimulant poisoning specifics

• Which toxidrome: metamfetamine is mainly adrenergic and dopaminergic (sympathomimetic toxidrome); MDMA is mainly serotonergic (can present as serotonin toxicity).
• Toxic doses: more than 1 g of cocaine or metamfetamine is potentially lethal. Dexamfetamine, methylphenidate and phentermine <1 mg/kg, and pseudoephedrine <15 mg/kg, are unlikely to cause toxicity. Purity and adulterants make illicit doses unpredictable.
• PMA and PMMA (found as MDMA contaminants) can cause fatal hyperthermia and intracranial haemorrhage.
• Hyponatraemia (especially MDMA) from SIADH plus excess water intake; severe cases cause cerebral oedema and seizures. Fluid restriction corrects most within 24–48 h. Use hypertonic saline only for sodium <125 mmol/L with seizures or acutely altered mental state: sodium chloride 3% 100 mL IV over 10 min, repeated up to 300 mL total (adults).
• Other complications: pneumothorax, pneumomediastinum.
• Extra investigations: troponin if ischaemia suspected; chest X-ray if dissection, pneumothorax or pneumomediastinum suspected; CT brain for altered consciousness without clear cause, headache or focal signs; angiography for suspected vascular occlusion or dissection.
• Decontamination: limited role in recreational use. Activated charcoal may help in deliberate oral self-poisoning (e.g. MDMA) if alert and within 2 hours. Body stuffers and body packers: discuss with a clinical toxicologist.
• Disposition: admit anyone with sympathomimetic toxidrome until resolved; critical care for vascular complications or hyperthermia. Otherwise observe at least 4 hours (immediate-release) or 12 hours (modified-release, e.g. ADHD medicines).

Hallucinogens

• Management is supportive; there are no antidotes. Treat sedation, hyperthermia and complications by the relevant toxidrome.
• Investigations: ECG, UEC, CK, lactate.
• Admit if sympathomimetic or serotonin toxicity is present (ICU if hyperthermic). Otherwise observe at least 4 hours and until symptoms settle. Most recover within 12–24 hours; NBOMe can cause symptoms for days.
• Psychiatric relevance: persistent psychosis after resolution of intoxication needs assessment for a primary psychotic disorder.

Sources

• eTG Toxicology and Toxinology: Sympathomimetic toxidrome; Stimulant drug poisoning; Novel hallucinogenic drug poisoning (all published August 2020; accessed 8 Oct 2026).
• NSW Health. Management of patients with Acute Severe Behaviour Disturbance in emergency departments, GL2015_007 (cited in eTG).

MAOI toxicity and hypertensive crisis

Irreversible MAOIs (phenelzine, tranylcypromine) have a narrow therapeutic index and cause three emergencies: overdose, serotonin toxicity from drug combinations, and hypertensive crisis from tyramine or sympathomimetic drugs. Overdose toxicity is often delayed 6–24 hours, then can collapse abruptly. Call a clinical toxicologist or 13 11 26 early.

Three presentations

Reversible MAOIs (moclobemide) are usually less toxic and resolve faster. Weak MAOIs such as isoniazid and lamotrigine have their own eTG monographs.

Overdose: risk by dose (irreversible MAOIs)

Serum MAOI levels are not useful.

Overdose: clinical progression

• Early: headache, agitation, tremor, sinus tachycardia, mydriasis, hyperreflexia, hyperventilation.
• Worsening: hypertension, rigidity, hyperthermia, rhabdomyolysis, clonus, confusion.
• Severe: coma, seizures, hypotension (poor prognosis), worsening hyperthermia, DIC, life-threatening arrhythmias, cardiac arrest, multi-organ failure.

Investigations

FBC, UEC, CK, blood gas, coagulation profile, ECG (ST and T-wave changes), CT brain if intracranial haemorrhage is suspected (severe headache, focal signs, falling consciousness).

Management

1. Escalate: clinical toxicologist or 13 11 26.
2. Hypertension: titrated IV benzodiazepines first. If it persists, a short-acting agent (IV glyceryl trinitrate) because BP can swing rapidly. Doses as for Sympathomimetic toxicity.
3. Hypotension: IV fluids, then noradrenaline. Early bedside echo helps separate poor contractility from vasodilation. Avoid indirect sympathomimetics (e.g. metaraminol).
4. Arrhythmias: ALS protocols with toxicologist advice. Avoid beta blockers (unopposed alpha effect raises BP).
5. Hyperthermia (>39 °C or rapidly rising): rapid cooling, cold IV fluids first-line.
6. Seizures: IV benzodiazepine.
7. Serotonin toxicity: manage as in Serotonin toxicity.
8. Activated charcoal if alert, able to protect airway and within 2 hours; any time via NG or OG tube if intubated.
9. Avoid all serotonergic and indirect adrenergic drugs. Directly acting catecholamines (adrenaline, noradrenaline, dopamine) can be used cautiously with BP monitoring.

Disposition

• Serotonin toxicity from an MAOI: critical care.
• Ingestion >1 mg/kg, or MAOI plus a serotonergic or adrenergic drug: admit for at least 24 hours.
• Ingestion <1 mg/kg without co-ingestants: discharge if asymptomatic for at least 12 hours.
• Tyramine reaction: observe at least 4 hours after symptoms resolve; tyramine-free diet for 2 weeks.
• Advise no driving or operating machinery for at least 3 days.

Prevention: dietary and drug advice (eTG)

• Food should be fresh, stored properly and eaten soon after purchase. Cooking does not destroy tyramine.
• Continue restrictions for 14 days after stopping phenelzine or tranylcypromine.
• Moclobemide at recommended doses rarely needs dietary restriction (take after meals); restrictions apply at higher doses.
• Check every new medicine for interactions, including over-the-counter decongestants, cough medicines, tramadol and methylene blue. Patients should carry an MAOI alert.
• For switching to or from an MAOI, use an antidepressant switching resource (e.g. Psymatik).

Sources

• eTG Toxicology and Toxinology: Monoamine oxidase inhibitor (MAOI) poisoning (published August 2020; accessed 8 Oct 2026).
• eTG Psychotropic: Principles of using irreversible nonselective MAOIs, including Table 8.30 dietary guidelines (published March 2021; accessed 8 Oct 2026).

QTc prolongation and torsades de pointes

❤️ Open the QTc drug risk table

Drug-induced torsades de pointes (TdP) is rare, but psychiatric patients carry many risk factors at once. A QTc >500 ms or a rise >60 ms from baseline marks high risk. Treat it by removing the drug, correcting potassium and magnesium, and giving IV magnesium for TdP. No QTc value is an absolute bar to a needed psychotropic; weigh cardiac risk against psychiatric risk.

Definitions

• QT: start of QRS to end of T wave, measured in the lead with the longest interval using the tangent (maximum slope) method. Include large U waves fused to the T wave.
• Prolonged QTc: >440 ms in men, >460 ms in women (LITFL). APA uses Bazett-based bands: men normal <430, borderline 431–470, prolonged >470; women normal <450, borderline 451–480, prolonged >480.
• High risk of TdP: QTc >500 ms, or an increase >60 ms from baseline.
• Correction formula: Bazett over-corrects above 100 bpm and under-corrects below 60 bpm. Use Fridericia (QTcF) when heart rate is outside 60–100 bpm, and use the same formula for serial comparisons.
• In overdose: risk is better judged by the absolute QT plotted against heart rate on the QT nomogram (Chan, Isbister et al. 2007).
• Wide QRS: QT lengthens without a true repolarisation problem (bundle branch block, pacing, TCAs). Measure manually and interpret with care.

Torsades de pointes

Polymorphic VT with QRS complexes "twisting" around the baseline. Usually comes in self-limiting bursts causing palpitations, dizziness or syncope, but can degenerate into VF and sudden death. Think of it in any patient on QT-prolonging drugs with new syncope, palpitations, seizure or cardiac arrest.

Risk factors

eTG also lists: age 70 or older, history of syncope or palpitations, hypothyroidism, significant bradycardia, family history of sudden cardiac death or long QT, and baseline QTc above the upper limit of normal (440 ms males, 460 ms females). Risk is cumulative: a single non-cardiac drug rarely causes TdP on its own. QT prolongation is more likely with IV antipsychotics (e.g. for acute behavioural disturbance).

Psychotropics and QT risk

Common non-psychiatric culprits: macrolides, fluoroquinolones, ondansetron, antiarrhythmics, some antihistamines (hydroxyzine), azole antifungals. Use CredibleMeds as a starting list, but its evidence quality varies.

Citalopram and escitalopram dose limits

Avoid both in congenital long QT, known QT prolongation, or with other QT-prolonging drugs. Correct electrolytes and consider an ECG in cardiac disease. Reflex dose reductions in stable patients have been linked to more psychiatric admissions, so review rather than cut automatically.

Monitoring

• Antipsychotics (eTG): ECG before starting, unless therapy is expected to last less than 24 hours. If not possible in an acutely unwell patient, do it as soon as practical. If at risk, repeat once at steady state (after 3–5 half-lives), and again after dose increases or starting or stopping an interacting drug. Routine ECG annually on antipsychotics.
• Use an ECG from no more than 1 month before the decision, with no major change in medicines, electrolytes or cardiac status since.
• Check potassium, magnesium and calcium in anyone with vomiting, diarrhoea, eating disorders, alcohol use disorder, diuretics or PPIs.
• No ECG available should not by itself stop a needed psychotropic; weigh the known risks.

Management of QTc prolongation

1. Baseline QTc >500 ms before an antipsychotic (eTG): correct electrolytes, treat hypothyroidism, heart failure or bradycardia, refer suspected congenital long QT to a cardiac electrophysiologist, and stop or reduce other QT-prolonging drugs. Avoid high-risk agents (haloperidol, ziprasidone); choose a low-risk agent (aripiprazole). Regular ECGs and electrolytes; consider cardiology review.
2. During treatment, QTc >500 ms or rise >60 ms (eTG): address modifiable factors, then reduce the dose or switch to a lower-risk antipsychotic. If impossible or ineffective, continue with regular ECGs and electrolytes and consider cardiology review.
3. Admit for telemetry during drug withdrawal if there is syncope, ECG instability (ventricular ectopy, T-wave alternans, AV block, QRS widening), QTc >500 ms or a rise ≥60 ms (UpToDate), with a defibrillator immediately available.
4. Correct electrolytes: keep potassium in the high-normal range (about 4.5–5.0 mmol/L) and replace magnesium (first, if both are low).
5. Symptoms (syncope, palpitations, dizziness): urgent medical review and cardiac monitoring.

Management of torsades de pointes

1. Initial: continuous cardiac monitoring, IV access, 12-lead ECG, assess haemodynamic stability.
2. Pulseless or unstable: defibrillate (ALS) with IV magnesium.
3. IV magnesium sulfate for all TdP, even if serum magnesium is normal and even if the QT does not shorten. Give more slowly when there is a pulse, as rapid infusion can cause hypotension and asystole.
4. Stop all QT-prolonging drugs; correct potassium to the high-normal range.
5. Recurrent TdP despite magnesium: temporary transvenous overdrive pacing at about 100 bpm (preferred), with isoprenaline as a bridge to pacing. Isoprenaline worsens polymorphic VT that is not long-QT related, so confirm the diagnosis.
6. Avoid antiarrhythmics that prolong repolarisation; lidocaine is reserved for refractory cases.

Dosing (adults, UpToDate):

Magnesium sulfate 1 g is about 4 mmol. Children: magnesium 25–50 mg/kg bolus.

Sources

• eTG Psychotropic: Antipsychotic adverse effects, QT-interval prolongation and Table 8.31 (published March 2021, amended April 2026; accessed 8 Oct 2026).
• UpToDate: Acquired long QT syndrome: clinical manifestations, diagnosis and management (last updated October 2025; accessed 8 Oct 2026).
• Funk MC et al. APA resource document on QTc prolongation and psychotropic medications, 2018.
• LITFL. QT interval (Burns and Buttner, 2024), including the Chan, Isbister et al. QT nomogram (QJM 2007).
• MHRA Drug Safety Update. Citalopram and escitalopram: QT interval prolongation, 2011.
• Medsafe. Drug-induced QT prolongation and torsades de pointes: the facts, 2010.
• Thomas SHL, Behr ER. Pharmacological treatment of acquired QT prolongation and TdP. Br J Clin Pharmacol 2016;81(3):420–7.

Clozapine emergencies

Clozapine has five emergencies to know: neutropenia, myocarditis, gastrointestinal hypomotility, seizures, and toxicity when smoking stops. Gastrointestinal hypomotility now kills more patients than neutropenia. Fever or tachycardia in the first weeks, and abdominal pain or vomiting at any time, need same-day review.

At a glance

Neutropenia (Australian monitoring system)

• FBC weekly for the first 18 weeks, then monthly.
• Red range: daily FBC while red, protective isolation and haematology input if neutrophils are very low, treat infection urgently (febrile neutropenia pathway), consider G-CSF with haematology. Watch for rebound psychosis and cholinergic rebound after abrupt cessation.
• Patients with a red result are generally not rechallenged; rechallenge is possible only under a specialist and haematology protocol.
• Benign ethnic neutropenia uses lower thresholds (green neutrophils >1.5, red <1.0) when registered with the monitoring service.
• After missed doses: under 72 hours, no change; 72 hours to 4 weeks, extra weekly monitoring; 4 weeks or more, restart monitoring as a new patient.

Myocarditis (Ronaldson protocol)

• Baseline: troponin I or T, CRP, ECG, echocardiogram where available.
• Monitoring: troponin and CRP on days 7, 14, 21 and 28 (then weekly for 2 more weeks and 6-monthly per the ACSQHC chart), plus daily temperature, pulse and BP.
• Mild rise in troponin or CRP, persistent tachycardia, or infective symptoms: daily troponin and CRP until settled; clozapine can usually continue.
• Stop clozapine if troponin >2 × ULN or CRP >100 mg/L. Together these have an estimated 100% sensitivity for symptomatic myocarditis.
• Admit if confirmed; cardiology review and echo. Fever in the first 4 weeks needs urgent FBC and cardiac enzymes.
• Eosinophilia can accompany myocarditis.
• Rechallenge after myocarditis is a specialist decision with cardiology.

Gastrointestinal hypomotility

Clozapine combines antimuscarinic and 5-HT3 blockade, slowing the whole gut. Complications include faecal impaction, ileus, ischaemic bowel, perforation and sepsis; mortality is reported at 15–28%.

• Prevention: document baseline bowel habit; check bowel habit daily for 4 weeks then weekly; start an osmotic laxative (macrogol) with clozapine; add a stimulant (senna) if no bowel action for 48 hours; remove other anticholinergics; fibre, fluids, exercise.
• Emergency: abdominal pain, distension, vomiting, absent bowel sounds or overflow diarrhoea → withhold clozapine, urgent abdominal X-ray or CT, surgical review, IV fluids and nil by mouth as directed.
• Ask about bowels at every review; patients often do not report constipation.

Seizures

• Dose and level related; risk rises with high doses (e.g. >600 mg/day), rapid titration and high plasma levels.
• Manage the seizure as usual. Then check the clozapine level, arrange EEG and neurology review, consider anti-seizure medicine (valproate is contraindicated in women of childbearing potential; lamotrigine is an alternative), withhold clozapine for 1 day and restart at half the previous dose (ACSQHC).

Smoking, levels and toxicity

• Tobacco smoke (not nicotine) induces CYP1A2 and lowers clozapine levels substantially (by about 50%). Stopping smoking, including admission to a smoke-free unit, can cause levels to rise within days. Nicotine replacement does not prevent this. eTG notes the same effect for olanzapine and haloperidol.
• Other causes of rising levels: infection or inflammation, CYP1A2 inhibitors (fluvoxamine, ciprofloxacin), caffeine changes.
• Toxicity features: sedation, hypersalivation, confusion or delirium, myoclonus, seizures, hypotension, tachycardia.
• Action: record smoking status at every review and notify the medical officer of any change. eTG recommends therapeutic drug monitoring, where available, to guide the lowest effective dose: check a trough level (12 hours post-dose) before and after any change in smoking, and reduce the dose as levels and symptoms indicate.
• Restarting after >48 hours off: psychiatric review first, then restart at 12.5 mg once or twice daily and re-titrate (risk of hypotension, collapse and seizures).

Sources

• ACSQHC. NIMC clozapine titration chart user guide, 2023 (Australian monitoring ranges, schedules, adverse-effect actions).
• Ronaldson KJ et al. A new monitoring protocol for clozapine-induced myocarditis. Aust N Z J Psychiatry 2011;45(6):458–65.
• Clozapine rechallenge and initiation despite neutropenia: a practical guide. BMC Psychiatry 2020, Table 1 (benign ethnic neutropenia ranges).

Acute dystonia and akathisia

Acute dystonia is a frightening, sometimes airway-threatening muscle spasm that starts within minutes to days of a new or increased dopamine blocker. It responds within minutes to parenteral benzatropine. Akathisia is the commonest acute movement side effect to be mistaken for agitation, and giving more antipsychotic makes it worse.

Acute dystonia

• What it is: sustained or brief muscle contraction causing twisting movements or abnormal postures, often of the face, neck and trunk.
• Forms: torticollis, trismus, tongue protrusion, oculogyric crisis (fixed upward gaze), opisthotonus, and laryngeal or pharyngeal dystonia (stridor, dysphagia, breathlessness), which is an airway emergency.
• Who and when: most common in young males; within minutes to days of starting or increasing an antipsychotic, or starting or stopping an interacting drug. Also caused by antiemetics (metoclopramide, prochlorperazine, droperidol).
• Highest-risk drugs (eTG Table 8.31): haloperidol (+++); flupentixol, zuclopenthixol (++ to +++); chlorpromazine (++); asenapine, lurasidone (+ to ++). Lowest: clozapine (–), olanzapine and quetiapine (– to +).
• Differentials: seizure, tetanus, hypocalcaemia, functional (dissociative) disorder, stroke. Dystonia is usually painful, conscious and responds rapidly to an anticholinergic.

Management of acute dystonia

1. Laryngeal dystonia: treat as an airway emergency. Give parenteral benzatropine immediately, with oxygen and airway support; call for help.
2. Benzatropine IV or IM as below; expect relief within minutes. Repeat once after 20 minutes if no response.
3. Then switch to oral benzatropine for up to 2 weeks to prevent recurrence, tapering over the last few days.
4. Adjust therapy: stop or reduce other dopamine antagonists (e.g. metoclopramide), reduce the antipsychotic dose, or switch to an agent less likely to cause extrapyramidal effects.
5. Explain what happened; acute dystonia is distressing and affects future adherence. Document it as an adverse reaction.

eTG dosing:

Akathisia

• What it is: an unpleasant inner restlessness with an urge to move (pacing, rocking, shifting weight). Usually early in treatment or after a dose increase.
• Why it matters: often misread as worsening psychosis or agitation, leading to more antipsychotic. It is linked to distress, non-adherence and, in some reports, aggression and suicidality.
• Management (eTG): reduce the antipsychotic dose until it settles, or switch to an agent less likely to cause extrapyramidal effects. Only a small proportion respond to drug treatment; for intolerable akathisia in adults while adjusting therapy, consider one of the agents below. In children, seek specialist advice.

eTG dosing (adults):

Related movement effects (non-emergency)

• Parkinsonism: early weeks; reduce dose or switch; oral benzatropine 1–2 mg up to twice daily for up to 2 weeks while adjusting.
• Tardive dyskinesia: chronic choreiform movements, mainly orofacial. Reduce or switch; seek specialist advice for specific treatment.
• NMS: see NMS; rigidity with fever and altered consciousness is not dystonia.

Sources

• eTG Psychotropic: Antipsychotic adverse effects (acute dystonia, parkinsonism, tardive dyskinesia, akathisia; Table 8.31) (published March 2021, amended April 2026; accessed 8 Oct 2026).

Valproate emergencies

Valproate causes four emergencies: overdose (sedation to coma, with multi-organ toxicity at high doses), hyperammonaemic encephalopathy (which occurs at normal levels and normal liver function), hepatotoxicity, and pancreatitis. It is also highly teratogenic. Any new drowsiness, confusion, vomiting or ataxia on valproate needs a serum ammonia, not just a valproate level.

At a glance

Overdose (eTG)

Risk by dose:

• Levels: therapeutic 50–100 mg/L (350–700 micromol/L). Above 850 mg/L (6000 micromol/L) is associated with coma, respiratory depression and metabolic acidosis. Severe toxicity does not occur without sedation.
• Features: nausea, vomiting, abdominal pain, hepatotoxicity; drowsiness to coma, ataxia, seizures, cerebral oedema, respiratory depression; QT prolongation in large ingestions (torsades not reported), hypotension, tachycardia; hypoglycaemia, hypernatraemia (sodium load), hypocalcaemia; in severe toxicity, metabolic acidosis, raised lactate, hyperammonaemia and bone marrow suppression.
• Investigations: valproate level every 6 hours while consciousness is altered, until normal; UEC, calcium, blood gas, lactate, glucose, FBC, ECG, ammonia.

Management:

1. Airway: intubate and ventilate if consciousness compromises airway or breathing.
2. Hypotension: IV fluids first. If QT is prolonged, continuous ECG monitoring and serial 12-lead ECGs.
3. Activated charcoal for >200 mg/kg if alert, able to protect airway and within 4 hours; any time via NG or OG tube if intubated. Consider multiple-dose charcoal for >500 mg/kg, with a clinical toxicologist.
4. Haemodialysis early for life-threatening poisoning, with a clinical toxicologist: level >1000 mg/L (7000 micromol/L), or severe toxicity (pH <7.10, cerebral oedema, shock).
5. Carnitine for significant metabolic acidosis, cerebral oedema, hyperammonaemia or hepatotoxicity (weak evidence, biologically plausible, low harm).
6. Observation: at least 12 hours if >500 mg/kg; at least 8 hours if >200 mg/kg. Discharge when alert, ambulant and stable. No driving or operating machinery for at least 3 days.

eTG dosing (carnitine): 100 mg/kg IV initial dose, then 50 mg/kg IV every 8 hours until coma and metabolic acidosis resolve. Carnitine is not registered in Australia; it is available through the Special Access Scheme (check your state's emergency and life-saving drugs register).

Hyperammonaemic encephalopathy (at therapeutic doses)

• What it is: valproate inhibits the urea cycle (carbamoylphosphate synthetase-I) and depletes carnitine. Ammonia rises, brain glutamine increases and astrocytes swell, causing cerebral oedema.
• Can occur with normal valproate levels and normal LFTs. Ammonia levels correlate poorly with severity.
• Features: falling consciousness, lethargy, vomiting, cognitive slowing, confusion, ataxia, increased seizure frequency, focal neurological signs. EEG shows generalised slowing, sometimes triphasic waves.
• Risk factors: topiramate or phenobarbital co-prescription, urea cycle disorders (e.g. ornithine transcarbamylase deficiency), liver disease, carnitine deficiency, fasting or strict vegetarian diet, intellectual disability, long-term treatment.
• Management: stop valproate (and topiramate); check ammonia, LFTs and valproate level; exclude other causes of delirium; give carnitine (oral or IV 50–100 mg/kg/day in case series, or the eTG regimen above if severe); seek neurology or toxicology advice. Symptoms, EEG and ammonia usually normalise after withdrawal. Screen for a urea cycle disorder if it recurs or is severe.
• In psychiatric settings, VHE is easily mistaken for sedation, worsening mood disorder or catatonia.

Hepatotoxicity and pancreatitis

• Hepatic dysfunction occurs in more than 1%; fatal liver failure is rare and usually in the first 6 months. Highest risk: children under 2, polytherapy, metabolic or mitochondrial disease (avoid valproate in suspected mitochondrial disorders). Routine LFTs do not reliably predict liver failure, so warn patients about symptoms (malaise, anorexia, vomiting, jaundice, facial oedema). Stop valproate if hepatotoxicity is suspected; carnitine may help in severe cases.
• Pancreatitis occurs in less than 0.1% but can be fatal and can occur after years of use. Abdominal pain, nausea, vomiting or anorexia need prompt review and a lipase. Stop valproate if confirmed.
• Other serious effects: thrombocytopenia or altered platelet function (spontaneous bruising or bleeding needs review), SJS/TEN and DRESS, polycystic ovary syndrome, male infertility.

Pregnancy and women of childbearing potential

• RANZCP 2020: sodium valproate should be avoided in women of childbearing age (recommendation 10.7). Valproate and carbamazepine should be avoided in pregnancy.
• Valproate carries the highest risk among antiepileptics of major congenital malformations (including neural tube defects) and poor neurodevelopmental outcomes. Australian pregnancy category D.
• If there is no alternative: effective contraception, documented discussion of risk, the lowest effective dose (avoid ≥700 mg/day if possible), and high-dose folic acid (5 mg daily) before conception and in the first trimester. Do not stop abruptly after conception without specialist advice.
• Pregnant women on antiepileptic drugs can be referred to the Australian Pregnancy Register.

Monitoring and interactions

• Before starting: LFTs, FBC with platelets, pregnancy status and contraception, weight. Avoid in liver disease or a family history of it, urea cycle disorders and porphyria; reduce the dose in renal impairment.
• During treatment: measure ammonia for lethargy, vomiting or ataxia; FBC for bruising or bleeding; LFTs and lipase for symptoms. Levels help with suspected toxicity or adherence; take them at least 8 hours after the last dose.
• Key interactions: valproate roughly doubles lamotrigine levels (SJS risk; halve lamotrigine dosing); carbapenems sharply lower valproate levels (risk of relapse or seizures); topiramate increases hyperammonaemia; carbamazepine, phenytoin and phenobarbital lower valproate levels; large-dose aspirin raises them; valproate lowers olanzapine levels.

Sources

• eTG Toxicology and Toxinology: Sodium valproate poisoning (published August 2020; accessed 8 Oct 2026).
• Malhi GS et al. The 2020 RANZCP clinical practice guidelines for mood disorders. Aust N Z J Psychiatry 2021;55(1):7–117 (recommendation 10.7; perinatal section).
• Zawab A, Carmody J. Safe use of sodium valproate. Aust Prescr 2014;37:124–7.
• Segura-Bruna N et al. Valproate-induced hyperammonemic encephalopathy. Acta Neurol Scand 2006;114(1):1–7.
• Valproate-associated hyperammonemic encephalopathy. J Am Board Fam Med 2007;20(5):499 (carnitine dosing in case series).
• Sydney Children's Hospitals Network. Epilepsy clinician handbook: sodium valproate (hepatotoxicity risk groups).
• Psych Scene Hub. Clinical assessment and management of bipolar disorder (updated May 2025) (caution combining valproate with lamotrigine and in women of childbearing age).

Malignant catatonia

Malignant catatonia is catatonia with autonomic instability: fever, labile BP, tachycardia and tachypnoea. It can be fatal within days. Stop antipsychotics, give high-dose lorazepam, and move to urgent ECT if there is no rapid response.

Definition and relationship to NMS

• Catatonia is a psychomotor syndrome ranging from stupor to severe excitement. It can co-occur with delirium or coma.
• "Malignant" means clinically significant autonomic abnormalities (temperature, BP, heart rate, respiratory rate).
• Malignant catatonia was described long before antipsychotics existed. Many authors see NMS as a drug-induced form of the same syndrome, sharing reduced dopaminergic function in basal ganglia circuits.

Causes

• Psychiatric: bipolar disorder (more often than major depression), schizophrenia, other psychotic disorders.
• Medical: autoimmune encephalitis (including anti-NMDA receptor), systemic lupus erythematosus, CNS infection, metabolic disturbance, non-convulsive status epilepticus.
• Drug-related: antipsychotic exposure, abrupt benzodiazepine or other GABAergic withdrawal (including clozapine withdrawal).

Diagnosis

• DSM-5: at least 3 of 12 signs: stupor, catalepsy, waxy flexibility, mutism, negativism, posturing, mannerisms, stereotypy, agitation, grimacing, echolalia, echopraxia.
• Bush-Francis Catatonia Rating Scale: adds signs such as mitgehen, gegenhalten, ambitendency, automatic obedience and verbigeration. Use it to screen and to track response.
• Malignant features: fever, tachycardia, labile BP, tachypnoea, sweating, reduced consciousness.
• Lorazepam challenge: lorazepam 1–2 mg IV (or IM or sublingual), reassess with the Bush-Francis scale after 15–30 minutes. Rapid improvement supports the diagnosis; no response does not exclude it.

Investigations

• CK, FBC, UEC, LFTs, iron studies, TFTs, glucose, calcium, blood gas, drug screen.
• Look for medical causes: EEG (non-convulsive status), MRI brain, lumbar puncture with autoimmune encephalitis antibodies when the picture fits.
• Distinguish from NMS by history (antipsychotic exposure, timing) and from serotonin and anticholinergic toxicity by examination (see the Comparison table).

Management

1. Stop antipsychotics and other dopamine blockers (including antiemetics such as metoclopramide). They are contraindicated in malignant catatonia and raise NMS risk, especially with dehydration, parenteral or rapidly escalating doses, or previous catatonia.
2. Escalate: ICU for malignant catatonia (hyperthermia, severe hypertension, arrhythmias from electrolyte imbalance).
3. Start lorazepam and prepare for ECT at the same time (consent or legal authorisation, anaesthetic and medical review). If there is a substantive response within 24–48 hours, lorazepam can continue in place of ECT. If not, start ECT and stop the benzodiazepine. Mortality rises if ECT is delayed beyond about 5 days from onset.
4. Lorazepam dosing: do not withhold doses for sedation alone unless there is respiratory depression. Watch for respiratory depression with opioids or other sedatives; flumazenil reverses it.
5. Supportive care: IV fluids, cooling, nutrition (enteral if needed), VTE prophylaxis (DVT occurs in more than 25%, highest in retarded catatonia), pressure care with 2-hourly repositioning, aspiration precautions, bowel and bladder care, passive range of motion, monitor CK and renal function.
6. Treat the cause: e.g. immunotherapy for autoimmune encephalitis, restarting a withdrawn benzodiazepine or clozapine.
7. After remission: continue oral lorazepam at the effective dose for 3–6 months, then taper. Keep it going if an antipsychotic is reintroduced for the underlying illness; reintroduce cautiously and only once eating, drinking and moving normally.
8. Refractory, or ECT unavailable or declined: case reports support memantine, amantadine (may worsen psychosis), zolpidem, carbamazepine, topiramate, valproate or rTMS.

Lorazepam dosing (adults, UpToDate):

Remission with a benzodiazepine typically takes 4–10 days.

ECT

• Indication: first-line for malignant catatonia; also for non-malignant catatonia not responding to a benzodiazepine within about 1 week. RANZCP lists catatonia and NMS as established indications.
• Response: in a small case review, 9 of 11 patients with malignant catatonia responded to ECT versus 2 of 5 to a benzodiazepine. Overall, benzodiazepines, ECT or both achieve recovery in about 60–80% of catatonia.
• Technique (UpToDate): bitemporal placement and brief pulse are preferred. Usually three times a week; in malignant catatonia, daily until physiologically stable (often 2–5 treatments). Give at least 6 treatments to reduce sudden relapse; most remit within 6–12. If response plateaus, continue ECT and restart the same benzodiazepine, then check ECT quality and re-examine the diagnosis.
• Anaesthesia: use a non-depolarising muscle relaxant (e.g. rocuronium) in immobile patients with muscle damage, because suxamethonium can cause hyperkalaemia. Flumazenil before ECT may be used to reverse benzodiazepine anticonvulsant effect.
• Consent: follow the relevant mental health legislation where capacity is absent or the patient is involuntary.

Complications

Dehydration, malnutrition, aspiration pneumonia, DVT and PE, pressure injuries, faecal impaction, urinary retention, rhabdomyolysis and AKI, contractures. Malignant catatonia can leave lasting cognitive deficits, apathy or limb contractures; mortality may reach 20% (renal failure, thromboembolism, sepsis). Non-malignant catatonia generally has a good prognosis, especially with mood or toxic-metabolic causes; it can persist for years in schizophrenia and may recur.

Sources

• UpToDate: Catatonia: treatment and prognosis (last updated October 2025; accessed 8 Oct 2026).
• RANZCP. Professional practice guideline for the administration of ECT, 2019.
• Connell J et al. Malignant catatonia: a review for the intensivist. J Intensive Care Med 2023.
• Mann SC et al. Catatonia, malignant catatonia and NMS. Curr Psychiatry Rev 2013;9(2):111–19.

Quick comparison: hyperthermic drug emergencies

The fastest bedside discriminators are onset, tone versus clonus, reflexes, pupils, skin and bowel sounds.

Malignant catatonia and NMS overlap, and some regard NMS as a drug-induced form of malignant catatonia. Both respond to benzodiazepines and ECT.