Drug-induced delirium and agitation

At a glance

• Medicines are among the commonest reversible causes of delirium, and often one of several. Every delirious patient needs a medicine review including over-the-counter, complementary and illicit drugs.
• The bedside question is which toxidrome: anticholinergic, sympathomimetic, serotonergic, neuroleptic malignant, sedative, or withdrawal. Skin, pupils, tone, reflexes and bowel sounds sort most cases.
• Hypoactive delirium from sedatives, opioids and hyponatraemia is missed more often than the agitated kind.
• Treat the cause. Choose sedation by mechanism: benzodiazepines for withdrawal, stimulant and anticholinergic toxicity; antipsychotics only when distress or danger can't be managed otherwise.
• Screening, prevention and the general approach to delirium are in Approach to memory disturbance. Sedation doses and restraint law are in Significant behavioural issues.

Causes

Prescribed medicines

Group	Examples and the trap
Anticholinergics	Oxybutynin, amitriptyline, promethazine, benztropine, hyoscine, chlorpromazine, doxylamine. Burden adds up across drugs
Sedatives	Benzodiazepines, Z-drugs, gabapentinoids (accumulate in renal impairment)
Opioids	Pethidine is worst. Morphine and codeine metabolites accumulate in renal failure; oxycodone or fentanyl are better tolerated
Corticosteroids	Mood change to psychosis, more likely above prednisolone 40 mg daily
Dopaminergic drugs	Levodopa, dopamine agonists, amantadine (renally cleared)
Antiseizure drugs	Valproate (hyperammonaemia with normal LFTs), phenytoin and carbamazepine toxicity
Antimicrobials	Cefepime and carbapenems in renal impairment, fluoroquinolones, metronidazole encephalopathy, high-dose aciclovir
Narrow therapeutic index	Lithium, digoxin, theophylline
Metabolic via a drug	Hyponatraemia (SSRIs, thiazides, carbamazepine), hypoglycaemia (sulfonylureas, insulin), hypercalcaemia (calcium and vitamin D)
Cancer therapy	Ifosfamide encephalopathy, immune checkpoint inhibitor encephalitis or hypophysitis, CAR-T cell neurotoxicity (ICANS)
Baclofen	Renally cleared. In CKD it causes confusion, then coma and seizures

Poisoning

• Anticholinergic: antihistamines, quetiapine and olanzapine, tricyclics, datura and other plants.
• Sympathomimetic: methamphetamine, cocaine, MDMA, synthetic cathinones. See Overdose or toxic effects of illicit drug use.
• Serotonin toxicity: SSRIs, SNRIs, tramadol, MAOIs (including moclobemide and linezolid), MDMA.
• Synthetic cannabinoids, lithium (acute or chronic), salicylates, and carbon monoxide.

Withdrawal

Substance	Onset after last dose
GHB	1 to 6 hours
Alcohol (delirium tremens)	48 to 72 hours
Short-acting benzodiazepines	1 to 2 days; longer-acting agents several days to a week
Intrathecal baclofen	Hours after pump failure; itch, fever, rigidity, rhabdomyolysis
Nicotine	Hours; agitation rather than true delirium

Alcohol, benzodiazepine and GHB withdrawal are managed in Substance use disorders.

Focused history

• What changed and when: new drugs, dose increases, missed doses, a stopped benzodiazepine or alcohol on admission. Most drug delirium follows a change in the previous few days.
• Collateral: baseline cognition, alcohol and drug use, access to tablets, and the pharmacy dispensing history. Count the anticholinergics.
• Renal function over the past week. A fall in eGFR turns a safe dose of gabapentin, baclofen, cefepime or morphine into a toxic one.
• Timing: onset within hours points to poisoning, serotonin toxicity or GHB withdrawal. Onset over days to weeks fits NMS, lithium accumulation or hyponatraemia.

Focused examination

Feature	Anticholinergic	Sympathomimetic	Serotonin toxicity	NMS	Withdrawal
Skin	Dry, flushed	Sweaty	Sweaty	Sweaty	Sweaty
Pupils	Dilated, sluggish	Dilated	Dilated	Normal	Dilated
Bowel and bladder	Silent abdomen, retention	Normal	Diarrhoea, hyperactive	Normal	Normal or diarrhoea
Tone and reflexes	Normal	Normal or increased	Clonus, hyperreflexia, legs more than arms	Lead-pipe rigidity, reduced reflexes	Tremor
Onset	Hours	Minutes to hours	Within 24 hours of a dose change	Days to weeks	By drug
Speech and behaviour	Mumbling, picking at the air, visual hallucinations	Paranoia, pressured	Agitation	Mutism, catatonia	Tremulous, fearful

• Check the temperature, a bladder scan, pupils, skin in the axillae, and look for clonus at the ankles and eyes.
• Coarse tremor, ataxia and myoclonus in a patient on lithium suggest toxicity even with a level in range.

Pitfall: calling a sweaty, clonic patient "anticholinergic" because the pupils are large. Sweating and clonus point to serotonin toxicity.

Red flags

• Temperature over 39°C with rigidity or agitation: serotonin toxicity, NMS, stimulant toxicity, anticholinergic toxicity with exertion, or withdrawal. Cool, sedate and call ICU.
• QRS over 100 ms or a terminal R wave in aVR: sodium channel blockade (tricyclics, high-dose diphenhydramine). Physostigmine is contraindicated.
• Fluctuating consciousness with subtle twitching after a beta-lactam or ifosfamide: non-convulsive status.
• Delirium within hours of admission in a regular GHB, alcohol or benzodiazepine user.
• New focal signs, head injury on anticoagulants, or fever with meningism. Don't blame the drugs until these are excluded.

Investigations

• Glucose at the bedside, then sodium, calcium, magnesium, creatinine, LFTs, CK and a venous gas with lactate.
• Drug levels where they change management: lithium, digoxin, carbamazepine, valproate, phenytoin (correct for low albumin, or measure the free level), theophylline. Paracetamol and salicylate if poisoning is possible.
• Ammonia on valproate, even with normal liver tests.
• 12-lead ECG: QRS, QTc, bradycardia or heart block (digoxin, lithium).
• EEG if consciousness fluctuates without explanation, especially on cefepime, ifosfamide or after a seizure.
• CT brain for focal signs, falls or anticoagulation. Urine drug screens rarely change management and miss many agents.

Management

General

• Follow the Delirium Clinical Care Standard (ACSQHC 2021): screen with a validated tool such as the 4AT, find and treat causes, use non-drug measures first, avoid restraint, and give antipsychotics only when the person is distressed or at risk of harm.
• Stop or reduce the culprit. Replace anticholinergics, switch morphine to a non-renally cleared opioid in AKI, and dose-adjust for renal function.
• Non-drug care: reorientation, glasses and hearing aids, sleep, mobilisation, hydration, bowel and bladder care, family at the bedside. The Hospital Elder Life Program (Inouye, NEJM 1999) cut incident delirium from 15% to 9.9% in older inpatients.

Specific treatments

Cause	Treatment
Anticholinergic delirium	Physostigmine 0.5 to 1 mg IV slowly, repeated, on toxicologist advice; cardiac monitoring. Benzodiazepines if it isn't available or is contraindicated. Rivastigmine when physostigmine is unavailable or delirium recurs: in a retrospective series of 50 patients from two Australian toxicology units (Chiew 2024), oral 6 mg needed further parenteral sedation or physostigmine less often than the patch (32% vs 73%). Observational evidence only
Stimulant toxicity	Benzodiazepines, droperidol for psychosis, active cooling
Serotonin toxicity	Stop serotonergic drugs, benzodiazepines, cyproheptadine for moderate cases, severe toxicity (temperature 38.5°C or higher and rising, with rigidity) needs intubation, paralysis and active cooling
NMS	Stop the antipsychotic, cool, fluids, benzodiazepines; bromocriptine or dantrolene in severe cases
Lithium or baclofen accumulation	Fluids and stop the drug; haemodialysis for severe neurotoxicity or renal failure
Valproate hyperammonaemia	Stop valproate; L-carnitine in severe cases
Sulfonylurea hypoglycaemia	IV glucose, then octreotide to stop recurrent hypoglycaemia
Withdrawal	Benzodiazepines (alcohol, benzodiazepines, GHB), reinstate baclofen

• Flumazenil isn't used to wake an undifferentiated delirious or comatose patient. It can provoke seizures in dependence and mixed overdose.

Sedation

• Antipsychotics don't treat delirium. MIND-USA (2018) found haloperidol and ziprasidone no better than placebo for ICU delirium, and AID-ICU (2022) found no benefit of haloperidol on days alive out of hospital.
• If distress or danger persists after non-drug measures, NICE CG103 allows short-term haloperidol at the lowest effective dose, usually for a week or less. Starting doses in older people come from Therapeutic Guidelines and local protocols rather than NICE: typically haloperidol 0.25 to 0.5 mg, or olanzapine 2.5 mg.
• Avoid antipsychotics in anticholinergic delirium (they add anticholinergic effect and lower the seizure threshold), in NMS, and in Parkinson disease or Lewy body dementia, where low-dose quetiapine is the least harmful choice.
• Benzodiazepines worsen delirium except in withdrawal, stimulant, serotonin and anticholinergic toxicity, where they are the treatment.

Special populations

• Older people: the Drug Burden Index and anticholinergic burden scores predict falls and cognitive decline. Deprescribe at discharge and tell the GP what was stopped and why.
• Renal impairment: gabapentinoids, baclofen, cefepime, morphine, pethidine, amantadine and lithium accumulate.
• Parkinson disease: sudden withdrawal of levodopa (nil by mouth, missed doses) causes confusion and an NMS-like state. Give doses on time, using a nasogastric tube or rotigotine patch when needed.

Pitfalls

• Treating anticholinergic delirium with haloperidol or olanzapine.
• Giving physostigmine with a wide QRS.
• Missing urinary retention in an agitated older man on oxybutynin or amitriptyline.
• Accepting a "therapeutic" lithium level in a patient with coarse tremor and confusion.
• Blaming dementia for a decline that started with a new gabapentin or opioid dose.
• Normal LFTs leading you away from valproate as the cause.
• Calling akathisia "agitation" and giving more of the antipsychotic that caused it.