Delirium & antipsychotic pharmacology (2024)

Delirium

• Delirium mimics
• Causes
• Diagnostic approach
• Treatment

Antipsychotic use in acute care

• Antipsychotics – overview
• Olanzapine
• Quetiapine
• Chlorpromazine
• Risperidone
• Lurasidone

definition & diagnosis

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definition

• Delirium is acute, generalized brain dysfunction (“cerebral insufficiency”). Key features:
  • Acute (e.g. not dementia).
  • Causes inattention (e.g. disorientation, inability to perform complex tasks).
  • Tends to wax and wane: may have periods of lucidity in between periods of confusion.
  • Not due to severely reduced level of arousal (i.e., coma).
• Encephalopathy is defined as a broader term referring to any rapidly developing, diffuse neurological dysfunction (which encompasses both delirium and coma).(33184265)

common features of delirium

• Delirium may be sub-classified:
  • Hyperactive delirium: agitation.
  • Hypoactive delirium: patient is withdrawn, mute, drowsy. This can often fly under the radar because it's not overtly problematic.
  • Mixed delirium: periods of hyperactive delirium & hypoactive delirium.
• Features can include:
  • Psychotic symptoms (hallucinations, delusions, paranoia).
  • Emotional symptoms (fear, anxiety, irritability, anger).
  • Sundowning (day-night reversal with hyperactivity at night).
  • Increased sympathetic activity (hypertension, tachycardia).

epidemiology

• Delirium is extremely common among critically ill patients (affecting ~50-80% of patients).(33758677)
• Risk of delirium correlates with:
  • Older age.
  • Low cognitive reserve (e.g., baseline dementia).
  • Comorbidities (including alcohol or substance use disorder).
  • Illness severity (especially intubation).

delirium screening? (CAM-ICU)

• CAM-ICU is a bedside test to detect delirium among ICU patients. It is often used in clinical research.🧮
• It has become popular to test CAM-ICU routinely for ICU patients. However, there is no solid evidence that this improves outcomes.
• The 2018 SCCM guidelines concluded that evidence doesn't establish whether delirium screening is beneficial, and thus they made no recommendation regarding this.(30113379)
• Application of the CAM-ICU test several times a day represents a significant workload for the bedside nurse.
• Rather than screening for delirium, the best global strategy to reduce delirium in the ICU is to apply delirium prevention strategies to all patients in the ICU. Evidence supporting primary prevention of delirium is more robust than evidence supporting early detection and intervention.(12389836)

delirium mimics

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We are often very quick to jump to the diagnosis of delirium. However, several other pathologies may mimic delirium. A few notable ones are:

• Catatonia. 📖
• Abulia / akinetic mutism. 📖
• Various aphasias (especially mild Wernicke aphasia).
• Acute ischemic stroke can rarely mimic delirium:
  • PCA (posterior cerebral artery) stroke. 📖
  • Dominant inferior division MCA stroke can rarely mimic delirium, if the Wernicke's aphasia is missed. 📖
• Stupor/coma. 📖

causes

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Delirium can reflect a broad range of neurologic or systemic aberrations. All contributory factors should be sought out and managed. Common causes are listed here, but this list isn't exhaustive.

medications

• ⚠️ Especially look for:
  • New medications.
  • Drug-drug interactions.
  • Renally cleared medications plus acute kidney injury.
• Benzodiazepines (perhaps the single worst offender that is consistently associated with delirium).
• Zolpidem (AMBIEN) and related sleep medications.
• Antihistamines, especially 1st generation (e.g., diphenhydramine, promethazine, hydroxyzine).
• Anticholinergics (e.g., tricyclic antidepressants, scopolamine, atropine).
• Opioids (low-dose opioid as used appropriately for pain may reduce delirium, but opioids dosed excessively or used inappropriately as a sedative will exacerbate delirium).📖
• Antiseizure medications(carbamazepine, phenytoin, valproate).
• Antispasmodics (especially baclofen).
• Antimicrobials (especially fluoroquinolones 🌊, cefepime).
• Steroid.
• H2-blockers (e.g., famotidine).
• Metoclopramide.
• Parkinson's disorder medications. 📖

toxicologic

• Withdrawal from EtOH, benzodiazepines, gabapentin, baclofen, opioid, serotonin-norepinephrine receptor inhibitors, dexmedetomidine.
• Intoxication from nearly any substance (e.g., sympathomimetics, carbon monoxide, lithium, digoxin).
  • Chronic salicylate intoxication in elderly may be a subtle cause.

organ failure & metabolic

• General: Fever 📖 or hyperthermia 📖.
• Cardiovascular:
  • Shock.
  • PRES (Posterior Reversible Encephalopathy Syndrome). 📖
  • Congestive encephalopathy. 📄 (32624312)
• Pulmonary: Hypercapnia.
• Gastrointestinal/Liver:
  • Hepatic encephalopathy.
  • Accumulation of hepatically cleared medications.
  • Hyperammonemia not due to cirrhosis (rare, yet occasionally seen).
  • Wernicke encephalopathy. 📖
• Renal:
  • Uremia.
  • Accumulation of renally cleared medications.
  • Electrolyte abnormality (especially dysnatremias, hypercalcemia).
• Endocrine:
  • Hypoglycemia 📖, DKA 📖, or hyperosmolar hyperglycemic state 📖.
  • Thyroid storm, or myxedema coma.
  • Adrenal crisis.
• Any significant infection (e.g., urinary tract infection, pneumonia).

neurological primary process, e.g.:

• ICH (intracranial hemorrhage).
• Ischemic stroke.
• Infection (meningitis, encephalitis).
• Autoimmune encephalitis. 📖
• TBI (traumatic brain injury).
• Intermittent seizures or nonconvulsive status epilepticus (NCSE). 📖

sleep deprivation

• Noisy ICU environment.
• Frequent blood pressure or neurologic checks.
• Uncontrolled pain.

diagnostic approach

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See Also

Quetiapine: Uses, Dosage, Side Effects, Warnings - Drugs.comThe Life Of DomitianLatin Inscriptions on Fine Art Works of Allegory GenreПеревод succession of vowels and consonants со всех языков на английский

initial assessment

• STAT fingerstick glucose.
• Vital signs, neuro exam (? attention, ? focal deficits).
• Review current medication list.
• Review home medication list (withdrawal?).
• Review recent events & procedures.

consider indications more in-depth workup

• Delirium is common in ICU; not every patient requires a huge workup.
• Some indications for more aggressive evaluation:
  • Rapid & major change in mental status.
  • Delirium was the presenting problem to the hospital.
  • No obvious cause for the delirium.
  • No history of prior delirium/dementia.

labs to consider

• Basics:
  • 🚨 Fingerstick glucose (STAT).
  • Electrolytes (including Ca/Mg/Phos).
  • CBC with differential.
• Consider, depending on context:
  • Levels of medications the patient is on (e.g., lithium, digoxin, phenytoin, theophylline, valproic acid, phenobarbital).
  • Liver function tests.
  • Ammonia.
  • TSH (thyroid stimulating hormone).
  • ABG/VBG (if hypercarbia suspected).
  • Infectious workup (e.g., urinalysis, blood cultures, chest X-ray). 📖
  • Toxicologic workup (e.g., carboxyhemoglobin, salicylates, acetaminophen). 📖

consider neuroimaging

• Nonenhanced CT head may be considered, especially for:
  • Patients presenting with delirium, especially if the history is unclear.
  • History of trauma.
  • Significant anticoagulation.
  • Focal neurologic abnormality (note however that subdural hematoma can depress mental status without focal findings).
  • Substantially reduced level of consciousness.
• MRI may provide additional information about a variety of conditions (especially CVA).

consider lumbar puncture, especially if:

• Delirium is chief complaint on admission to hospital.
• Evidence of infection (fever, leukocytosis, nuchal rigidity).
• 🛑 Among patients who develop delirium within the hospital, CNS infection is uncommon (unless there is an obvious precipitating factor, such as neurosurgery or endocarditis).(9332525)

consider EEG, especially if:

• History of seizure or active neurologic disorder that predisposes to seizure.
• Exam concerning for nonconvulsive status epilepticus. 📖
• Delirium remains unexplained despite other investigations.
• (Discussion of EEG to sort out delirium vs catatonia is here: 📖)

treatment overview

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There is no single treatment for delirium. Management involves elimination of the causes of delirium, while keeping the patient safe.

(#1) remove all treatable causes of delirium, e.g.:

• Stop iatrogenesis:
  • Remove unnecessary invasive devices.
  • D/C deliriogenic medications. 📖
• Correct metabolic disorders, especially:
  • Hypoglycemia. 📖
  • Hypernatremia. 📖
  • Wernicke encephalopathy: If this is possible, empiric thiamine 500 mg IV q8hr.📖
  • Hepatic encephalopathy: If this is probable, empiric treatment may be reasonable.
• Pain management with multimodal analgesia (including scheduled acetaminophen). 📖
• Fever treatment, if fever seems to be promoting confusion. 📖

(#2) treat dangerous agitation (if present)

PRN IV butyrophenones (haloperidol/droperidol) 💉

• These are often used as initial therapy for dangerous agitation.
• Advantages include rapid efficacy and immediate availability.
• Contraindications include:
  • Known QT prolongation.
  • Parkinson disease or Lewy body dementia.
• Prolonged administration may increase toxicity, so these agents are ideally used only intermittently, for breakthrough agitation.

dexmedetomidine 💉

• Dexmedetomidine has numerous advantages:
  • Titratability, which may be especially useful for treating nocturnal agitation (“sundowning”).Dexmedetomidine can be to treat nocturnal agitation and promote sleep at night. The following day, dexmedetomidine can be titrated off, thereby promoting wakefulness during the day.(29498534) The short half-life of dexmedetomidine avoids the sundowning cycle wherein a patient gets tons of medications for agitation at 2 AM, sleeps for 18 hours, and then wakes up and gets agitated the following night.
  • Lack of respiratory depression.
• The main disadvantage of dexmedetomidine is that it takes some time to work, so it's not a good option for acute, dangerous agitation. Additional drawbacks include risks of bradycardia and hypotension.

sedating atypical antipsychotics

• Sedating atypical antipsychotics have some advantages:
  • Superior side-effect as compared to prolonged, high-dose haloperidol.Thus, gradual escalation of scheduled atypical antipsychotics as a haloperidol-sparing agent may lead to an overall safer antipsychotic regimen.
  • May be continued outside of the ICU (for patients with ongoing delirium).
• A useful combination is often PRN IV haloperidol plus scheduled atypical antipsychotic.
• Quetiapine 💉 might have the best overall side-effect profile, but olanzapine 💉 has advantages for some patients (e.g., lack of QTc prolongation, more flexible routes of administration).

(#3) promote sleep & circadian rhythm

basic sleep maintenance

• Stimulate during the day:
  • Use patient’s glasses and hearing aides if needed.
  • Physical therapy.(31724092)
  • Open window shades.
• Limit stimulation at night:
  • Using ear plugs at night has been shown to avoid delirium.(31724092) This should arguably be done for all ICU patients, if tolerated.
  • Decrease the frequency of vital sign monitoring at night if possible (especially blood pressure cuff cycling). 🌊
  • Use of single ICU rooms that are quieter.
  • Schedule phlebotomy during the day (not 5 AM).

pharmacologic insomnia treatment

• Preferred medications are:
  • Quetiapine 25-50 mg PO QHS might be the best agent. 📖
  • Trazodone 💊 25-100 mg PO QHS:
    • Trazodone is generally regarded as a delirium-friendly treatment for insomnia, but little evidence is available regarding its use in the ICU.
    • Peak serum levels occur ~1 hour after ingestion.
    • Contraindications/side effects of note: QT prolongation, torsade de pointes, orthostatic hypotension, promotion of serotonin syndrome.
  • Dexmedetomidine: Low-dose, nightly dexmedetomidine is arguably the most effective agent to promote sleep and daytime wakefulness (as discussed further in the section above). Unfortunately, logistics often prevent dexmedetomidine from being broadly implemented for management of insomnia.
• Melatonin does not appear to prevent delirium, based on the largest and most robust multi-center RCT that evaluated 4 mg QHS (Pro-MEDIC trial).📄 However, melatonin may still be utilized for management of insomnia.
• ⚠️ Avoid using of deliriogenic sedatives (e.g., benzodiazepine, diphenhydramine, or zolpidem).

antipsychotics

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role of antipsychotics in treatment of delirium?

• Antipsychotics probably don't really fix the underlying delirium. However, they may be useful to manage symptoms that are acutely dangerous or impairing patient recovery. For example:
  • Treatment of dangerous agitation.
  • Management of insomnia.
• 💡 Antipsychotics are not beneficial in patients with hypoactive delirium.(30346242) For example, haloperidol was ineffective in the MINDS-USA trial, likely because 89% of patients in this trial had hypoactive delirium.(30346242) 🌊

how are these drugs actually working?

• Antipsychotics are dirty drugs that interact with a lot of different receptors.
• Typical antipsychotics predominantly block the D2 dopamine receptor. Alternatively, atypical antipsychotics block the 5-HT-2A receptor, with less pronounced blockade of the D2 dopamine receptor.
• Although classified together, antipsychotics have diverse mechanisms of action. Thus, if a patient fails to respond to one antipsychotic, this doesn't indicate that they will be refractory to all antipsychotics. For example, a patient might not respond favorably to haloperidol but subsequently respond well to chlorpromazine. This makes sense, considering that chlorpromazine's receptor activities mimics a combination of quetiapine plus haloperidol.

role of antipsychotics vs. sedatives for agitation in the intubated patient?

• In a perfect world, we would be able to clinically differentiate between delirium and anxiety at the bedside. Delirium would be treated with an antipsychotic, whereas anxiety would be treated with a sedative. Unfortunately, sorting this out can be impossible – especially among intubated patients. To blur the line between psychosis and anxiety even further, many antipsychotic agents have strong sedative effects.
• Pragmatically, our goal is to render patients comfortable with a medication regimen that will cause the least amount of iatrogenic harm. This may often involve a certain degree of trial and error, to determine which medication the patient responds best to.
• For difficult-to-calm patients, a multimodal combination of sedatives plus an antipsychotic may be useful. By using low-to-moderate doses of different agents, side effects may be avoided. Meanwhile, efficacy may be maximized if different agents function synergistically. Unfortunately, to date there is minimal research available about how to optimally combine numerous medications (research generally focuses on a single agent).

some general concepts on antipsychotic use

• (1) Patients may respond variably to different agents. If a patient isn't responding favorably to one agent, it may be better to switch to another agent rather than continuing to up-titrate the dose.
• (2) Optimal dose ranges for ICU patients are largely undefined. Among outpatients, antipsychotics are generally started at a low dose and up-titrated. This may be a rational approach among critically ill patients as well. Overly aggressive up-titration may increase the risk of neuroleptic malignant syndrome.📖
  • At very high doses, many drugs will start to lose relative receptor selectivity, leading to a higher rate of side-effects (figure below). Thus, the optimal dose may often lie within the middle of the dosing range (not at the maximal dose).
• (3) Obtaining a psychiatric history of the patient can be invaluable:
  • Restarting a patient's home psychiatric medication regimen can often be invaluable.
  • Some patients have chronic, untreated schizophrenia or bipolar disorder. These patients especially might benefit from antipsychotics (sometimes in combination with valproate).
• (4) The dose and duration should be limited as much as possible, without compromising patient comfort and safety. In particular, avoid sending patients home from the hospital on chronic antipsychotic therapy.

butyrophenones (haloperidol & droperidol)

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dosing and route

As a very rough rule of thumb, droperidol is ~2-3 times more potent as haloperidol. (27460622)

route

• Haloperidol: 💊
  • IV route is usually utilized preferred among critically ill (this carries a lower risk of dose-stacking or extrapyramidal side-effects, albeit with a higher risk of torsade de pointes).(3597329) With IV administration, onset occurs in ~10-15 minutes.
  • IM route can be used.
  • PO is not usually used in the ICU (atypical antipsychotics would generally be preferred for patients receiving oral antipsychotic therapy).
• Droperidol: IM or IV 💊

dose for agitation

• Haloperidol:
  • Dangerous agitation in young/robust patient: starting dose 10 mg IV/IM (often combined with midazolam).
  • Dangerous agitation in elderly patient: starting dose 5 mg IV/IM.
  • Milder agitation, not immediately dangerous: starting dose ~2.5 mg IV/IM.
  • Wait ~20 minutes prior to re-dosing.
  • If no response to cumulative dose of ~30 mg, then try a different medication.
• Droperidol:
  • Dangerous agitation in young/robust patient: starting dose 10 mg IV/IM alone.
  • Dangerous agitation in elderly patient: starting dose 5 mg IV/IM.
  • Wait ~20 minutes prior to re-dosing.
  • If no response to cumulative dose of ~20 mg, then try a different medication.

dose for nausea

• Haloperidol: The usual dose is 2-3 mg IM/IV. An additional dose may be provided if needed after 20-30 minutes. Subsequently, the effective dose may be repeated q4 hours PRN.
• Droperidol: The usual dose is 0.625-1.25 mg IV. An additional dose may be provided if needed after 20-30 minutes. Subsequently, the effective dose may be repeated q4 hours PRN.
• Especially useful: treatment/prevention of postoperative nausea/vomiting, cannabinoid hyperemesis syndrome. (32468935)

dose for procedural sedation

• ~2.5-5 mg of IV droperidol. (10805839; 10968851; 10425409)
• ~2.5-5 mg IV haloperidol. (30611640)

maximal dose?

• There is no clear “maximal dose” of haloperidol. Historically, massive doses were used with reasonable safety (e.g., >200 mg/day for up to two weeks!).(8124994) Given the potential for high doses of haloperidol to cause QT prolongation and extrapyramidal side effects, it's probably ideal to use much lower doses than that (perhaps <35 mg/day). Addition of scheduled atypical antipsychotics may reduce the requirement for high doses of haloperidol.

contraindications, toxicity, cautions

• [1] QTc prolongation and torsade de pointes can occur (but this is rare at the doses which are currently used). These agents are contraindicated in patients with known QTc prolongation. (If this is a problem, consider using olanzapine, which doesn't affect QT).
• [2] Extrapyramidal symptoms can occur:
  • These agents are contraindicated in patients with Parkinson's disease or Lewy Body Dementia.
  • Butyrophenones can cause dystonia or akathisia (disturbing restlessness). This generally isn't a major problem, but must be identified and treated appropriately. Akathisia must not be misdiagnosed as “agitation” and treated with escalating doses of antipsychotic agents!
• [3] Sedation may occur (especially when being used for nausea).
• Prolonged administration can cause tardive dyskinesia, so these aren't preferred as a maintenance antipsychotic (consider quetiapine or olanzapine instead).
• Neuroleptic malignant syndrome can occur (rarely).

indications and advantages

general advantages

• Hemodynamically stable agents.
• Immediately available on most units.
• Can be administered intravenously.
• More easily dose-titrated than most other antipsychotics.
• Do not suppress respiration (allowing them to be used for nonintubated patients).

use in agitated delirium

• These agents are a traditional mainstay of initial therapy for dangerous agitation (although dissociative ketamine may be preferred for the most profoundly dangerous patients).
• Butyrophenones may not be ideal for longer term management of delirium, due to a relatively high risk of extrapyramidal symptoms. An atypical antipsychotic (e.g., quetiapine or olanzapine) is generally preferable if ongoing maintenance therapy is needed, with IV haloperidol or IV droperidol utilized for PRN management of breakthrough agitation.

pharmacology and mechanism of action

pharmacology

• Haloperidol: Onset within ~20-30 minutes when given IV/IM. Oral bioavailability is 60%, with absorption within hours. Half-life is one day, but re-dosing is generally required sooner than that (e.g., within ~4-12 hours). Metabolized by numerous CYP pathways.
• Droperidol: Onset begins within ~10 minutes when given IM. Half-life is ~2 hours, with a duration of action of ~2-4 hours. Metabolized in the liver.

mechanism of action

• Butyrophenones exert strong effect on the dopamine receptors (antagonizing the D2 receptors). This generates more of a true antipsychotic effect, but also carries a greater side-effect profile (in terms of extrapyramidal side-effects and the risk of neuroleptic malignant syndrome).

olanzapine

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See Also

The Complete Works of Geoffrey Chaucer (volume 4)

dosing and route

route: olanzapine can be given by essentially all routes 💊

• PO (slowly absorbed).
• IM.
• IV (Like haloperidol, olanzapine isn't FDA labeled for IV administration. However, evidence supports that olanzapine can be given as a slow IV push, similar to haloperidol.) 🌊 🌊
• Oral disintegrating tablet (ODT).

dose for acute agitation

• Dangerous agitation:
  • Young/robust patient: 10 mg IM/IV.
  • Elderly or more fragile patient: 5 mg IV/IM.
• Acute agitation without immediate risk of danger: Smaller doses may be used, with titration to effect.
• Maximal total daily dose is ~20 mg.

dose for maintenance therapy of agitation/sedation on ventilator

• Maintenance therapy for agitated delirium: 5-20 mg PO daily, in the early evening. Oral olanzapine can take several hours to reach peak effect.(29915922)
• Administration in the early evening may encourage a normal circadian rhythm. The half-life of olanzapine is long enough that it will continue to exert some sedative effect during the day as well, but QHS dosing maximizes sedation at night.

dosing for nausea

• Antiemetic dose:
  • Start with 2.5 mg IV/IM.
  • If ineffective, an additional 2.5 mg dose may be given 30 minutes later.
  • The effective dose can be repeated q4hr PRN (with caution regarding the possibility of causing excessive sedation).
  • For ongoing nausea/vomiting, 5-10 mg PO QHS is often optimal. (31960161)
  • Maximal daily dose is 20 mg/day.
• Evidence:
  • Olanzapine has been demonstrated in RCTs to improve chemotherapy-induced nausea/vomiting when added to conventional therapy.
  • In one case series, olanzapine was highly effective among patients with nausea refractory to other agents. (26398872)

contraindications, toxicity, cautions

• 💡 Note that olanzapine doesn't cause torsade de pointes. 🌊 So this is a useful agent if the QT interval is prolonged.
• Olanzapine can cause extrapyramidal symptoms, although the risk is lower than with typical antipsychotics. Thus, Parkinson's disease or Lewy Body Dementia are a relative contraindication.
• ⚠️ Half-life may increase to ~50 hours in elderly patients, or patients with hepatic and/or renal dysfunction. Caution is required in such patients, to avoid drug accumulation that could lead to prolonged sedation and difficulty weaning from mechanical ventilation.

indications and advantages

• (1) IM/IV olanzapine can be used for acute agitation.
  • Main limitations: Not widely stocked in all units.
  • Advantage compared to haloperidol/droperidol: No risk of QT prolongation.
  • 💡 An advantage of the IV formulation is that it can help determine how the patient responds to olanzapine. For example, if 10 mg IV olanzapine has no effect on the patient, it's probably not the right medication for that patient.
  • One small RCT found that olanzapine was equally effective for management of delirium compared to haloperidol, while causing fewer extrapyramidal side-effects.(14685663)
• (2) PO olanzapine can be used as maintenance therapy for agitated delirium (especially for patients on mechanical ventilation). If provided in the early evening, the drug level will be highest at night, promoting a normal circadian rhythm.
  • Advantage of olanzapine compared to quetiapine: Lack of QTc prolongation.
  • Disadvantages of olanzapine compared to quetiapine: higher risk of extrapyramidal effects, less powerful sedative effects.
  • For most intubated patients, quetiapine may be a better choice.
• (3) Oral dissolving tablet (ODT) can be helpful in occasional situations (e.g., mild agitated delirium with insomnia in a patient who isn't intubated and isn't swallowing well).

pharmacology and mechanism of action

pharmacology

• Oral bioavailability is 60%, with relatively slow oral absorption over several hours.
• Half-life of ~30 hours (with a wide range of ~20-50 hours; metabolism is prolonged in elderly or patients with hepatic/renal dysfunction).
• Metabolized in the liver via CYP-1A2 and glucuronidation.

mechanism of action

• Olanzapine is the quintessential atypical antipsychotic used in critical care. It is generally well tolerated, aside from causing substantial sedation and occasional extrapyramidal effects. Olanzapine's relative lack of side effects may be explained by a balance of receptor activity:
  • A balance of activity against 5-HT2a receptors and D2 receptors reduces the risk of extrapyramidal side-effects (similar to other atypical antipsychotics).
  • Anticholinergic effects may further reduce the rate of extrapyramidal side-effects.

quetiapine

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route and dosing 💊

Quetiapine is only available enterally.

dosing for insomnia

• 25-50 mg QHS.

dosing for agitated delirium

• Usually start at 50 mg q12 hours and up-titrate as needed (typically increasing the dose by 50 mg each day). Generally don’t go higher than ~200 mg BID, but higher doses can occasionally be used (the maximal total daily dose is ~800 mg).(30005303)
• For patients with nocturnal agitation and/or insomnia, may use QHS dose only.
• ⚠️ Adjust for hepatic dysfunction, but not for renal dysfunction.(26033792)

contraindications, toxicity, cautions

• Of all the agents listed here, quetiapine might have the most benign side-effect profile overall.
• (1) Quetiapine can slightly prolong the QTc interval, but the risk of torsade de pointes seems to be extremely low. A review found only four reported cases of torsade de pointes associated with quetiapine (all of which occurred in the context of multiple other risk factors for torsades).(25057346) Caution is warranted in patients with QT prolongation, but it's overall dubious whether quetiapine truly causes torsades de pointes.
• (2) Quetiapine has the lowest risk of extrapyramidal side-effects (compared to other antipsychotics). For patients with Parkinson's disease, quetiapine may be the antipsychotic of choice since it has been shown to have no effect on the motor symptoms of Parkinson's disease.(28806160)
• (3) Quetiapine may cause hypotension due to antagonism of alpha-adrenergic receptors (more so than olanzapine).(28806160) This may cause orthostatic hypotension for patients who are mobile.

indications and advantages

• Insomnia: Seven-hour half life allows effects to wear off overnight.
• Longer term maintenance agent for agitation (especially during mechanical ventilation).
  • Quetiapine is arguably supported by the strongest evidence for this indication (infographic below).(19915454)
  • Quetiapine is very sedating, which could be useful for patients on mechanical ventilation.

pharmacology and mechanism of action

pharmacology

• Rapidly absorbed, within about an hour.
• Half-life of ~7 hours. However, an active metabolite (N-desalkyl quetiapine) has a 12-hour half-life, so the clinical effects will last longer.
• Metabolized in the liver via CYP-3A4.

mechanism of action

• At the lower doses, quetiapine may be working predominantly as a weak sedative (rather than an antipsychotic).(30181002) The overall result might be that quetiapine functions as a non-deliriogenic sedative. Indeed, quetiapine has demonstrated efficacy in generalized anxiety disorder.
  • The primary effect is sedation (via inhibition of histamine and acetylcholine receptors). Partial agonism of 5-HT-1A receptors may further promote anxiolysis.(G&G 13/286)
  • Normally, blockade of these receptors would promote delirium. However, atypical antipsychotics also have built-in antipsychotic activity (due to dopamine blockade) which prevents exacerbation of the delirium.
• At higher doses, quetiapine may have greater effects on dopamine and 5-HT2A receptors, thereby functioning similarly to other atypical antipsychotic agents.

chlorpromazine

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route and dosing 💊

• Schizophrenia, bipolar mania, agitated psychosis:
  • IV/IM: 25-50 mg, with an additional dose after one hour if needed. May slowly up-titrate as needed, to a maximal dose of 400 mg q4-6 hours. The usual dose range is 300-800 mg/day (divided ~q6hr).
  • Oral therapy: ~200-600 mg/day initially (divided ~q6hr), maintenance dose ~250-800 mg/day.
  • 100 mg/day oral chlorpromazine is very roughly equivalent to:(12823080; see also table below)
    • Haloperidol 2 mg/day.
    • Risperidone 2 mg/day.
    • Olanzapine 5 mg/day.
    • Quetiapine 75 mg/day.
    • Ziprasidone 60 mg/day.
    • Aripiprazole 7.5 mg/day.
• Nausea/vomiting: 10-50 mg PO/IV/IM q4-8 hours PRN (maximum dose 200 mg/day).
• Hiccups: 10-50mg, 3-4 times daily. May up-titrate to 50 mg 3-4 times daily (maximum dose 200 mg/day).

contraindications, toxicity, cautions

• Risk of extrapyramidal symptoms (contraindicated in Parkinson's disease or Lewy Body Dementia).
• May cause neutropenia, so contraindicated in leukopenia.
• Risk of QT prolongation and torsades de pointes (contraindicated in QT prolongation).
• Contraindicated in myasthenia gravis.
• May cause hypotension (chlorpromazine may cause relatively more inhibition of alpha-adrenergic receptors, compared to other antipsychotics).

indications and advantages

• Generally chlorpromazine is not a front-line agent. Uses include the following:
• (1) Agitated psychosis in a patient refractory to other medications (e.g., haloperidol, olanzapine) – especially if enteral access is unavailable. Chlorpromazine offers a broad spectrum of receptor activity, a high maximal dose ceiling, and the ability to be administered via IV/IM/PO routes.
• (2) Management of hiccups.
• (3) Antiemetic (but rarely used for this).

pharmacology and mechanism of action

pharmacology

• Bioavailability is ~25%, due to extensive first-pass metabolism by the liver. Thus, IV/IM doses are about four times more potent than oral doses (e.g., 25 mg IM is roughly equivalent to 100 mg PO). Oral doses are absorbed over a period of ~3 hours.(29929365)
• Metabolized by CYP-2D6. Chlorpromazine induces its own metabolism by CYP-2D6, causing levels to drop ~30% during weeks 1-3 of treatment. Individual pharmaco*kinetics may vary, depending on genetic variations in CYP-2D6.
• The duration of action is generally ~4-6 hours.
• When administered intravenously, the infusion rate is generally limited to 1 mg/min (to reduce the risk of hypotension or torsade de pointes).

mechanism of action

• Chlorpromazine is classified as a “typical” antipsychotic agent, but this designation doesn't quite capture it's mechanism of action. Chlorpromazine has a uniquely broad spectrum of receptor activity including strong inhibition of D2 receptors, strong inhibition of H1-histamine receptors, strong inhibition of 5-HT-2A receptors, and moderate anticholinergic activity. This combination give it powerful antipsychotic and sedating effects, allowing it to be effective for refractory agitated psychosis where other agents are ineffective.(30558470)
• The downside of this broad receptor profile is an increased side-effect profile (including extrapyramidal symptoms, and also hypotension that results from antagonism of alpha-1 adrenergic receptors).

risperidone

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route and dosing 💊

• Oral only (either as standard tablets or orally disintegrating tablets).
• Typical starting dose is 1 mg daily in the early evening. The usual dosing range is ~2-4 mg/day, with a maximum dose of ~6-8 mg daily.
• Dose reduction in hepatic or renal insufficiency.

contraindications, toxicity, cautions

• Extrapyramidal symptoms are more common than with other atypical antipsychotics (which might include a higher risk of tardive dyskinesia as well, if used chronically). Risperidone is contraindicated in patients with Parkinson's disease or Lewy Body Dementia.
• QTc prolongation and torsade de pointes can occur, albeit extremely rarely. Risperidone is contraindicated in patients with known QTc prolongation (if this is a problem, consider using olanzapine, which doesn't affect QT).

indications and advantages

• Risperidone may be used as an oral maintenance agent in agitated delirium, perhaps as a second-line agent. Its side-effect profile is a bit less favorable than other atypical antipsychotics (with a slightly higher incidence of extrapyramidal side-effects).
• Risperidone may be less sedating than other atypical antipsychotics (e.g., quetiapine, olanzapine). This could be useful in non-intubated patients with intermittent agitation due to an underlying psychiatric disorder (e.g., schizophrenia or bipolar disorder).

pharmacology and mechanism of action

pharmacology

• Rapid oral absorption within about an hour.
• Metabolized in liver by CYP-2D6 to an active metabolite (paliperidone).
• Half-life of ~20 hours (the half-life of risperidone is 3-4 hours, but the half-life or paliperidone is 20 hours).

mechanism of action

• Risperidone displays a relatively broad mechanism of action.
• Lack of anticholinergic effects is a double-edged sword:
  • Theoretically, anticholinergic activity may exacerbate delirium. It's unclear whether this is a clinically relevant problem for antipsychotics used at therapeutic doses in the ICU. However, theoretically a lack of anticholinergic effects could be beneficial for cognition.
  • Anticholinergic effects may reduce the tendency to develop extrapyramidal effects. Thus, a lack of anticholinergic effect may be one factor causing risperidone to have a higher rate of extrapyramidal effects (compared to olanzapine or quetiapine).
• Antagonism of central alpha-2A receptors might not be beneficial (note that dexmedetomidine and clonidine promote anxiolysis and sedation via stimulation of alpha-2A receptors).

lurasidone

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route and dosing 💊

• Oral only.
• Starting dose is 40 mg/day, ideally in the evening.
• Maximal daily dose is 160 mg.
• Dose reduction in hepatic or renal insufficiency (GFR < 50 ml/min).

contraindications, toxicity, cautions

• Exercise caution regarding drug-drug interactions with medications that affect the CYP3A4 system.
• Extrapyramidal symptoms may occur.
• Mania or hypomania may occur among patients with bipolar disorder.

indications and advantages

• Lurasidone may be used for management of agitated delirium.
• A primary advantage of lurasidone is that it doesn't affect QTc (similar to olanzapine).(22217440)
• Overall lurasidone isn't commonly used in the ICU. However, it could be useful in situations where other agents are contraindicated.

pharmacology and mechanism of action

pharmacology

• Oral bioavailability is 9-19% over 1-3 hours (increased by food).
• Metabolism is primarily hepatic, via CYP3A4.
• Half-life is ~18 hours, so steady state may not be reached for a few days.

mechanism of action

• Lurasidone has significant potency at the D2 receptors and also the 5-HT2A receptors (exerting both “typical” and “atypical” antipsychotic effects).
• Lurasidone lacks anticholinergic effects. This may be beneficial in terms of causing less confusion. However, anticholinergic activity tends to reduce extrapyramidal side-effects, so lurasidone theoretically could have a greater propensity for extrapyramidal side-effects.
• Lurasidone lacks antihistamine effects.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• DO NOT treat agitated delirium with a benzodiazepine. This will suppress symptoms temporarily, but will eventually make the delirium worse.
• Avoid benzodiazepines in general, with certain very specific exceptions (chronic benzodiazepine use, status epilepticus). The practice of using lorazepam for insomnia needs to be abolished.
• Don't overlook the cause of delirium, especially when it represents a dramatic neurologic change in a patient without any neurologic history. It may be the manifestation of a severe disease process (e.g. subdural hematoma, sepsis).
• Don't treat elderly, multimorbid ICU patients with the same doses of antipsychotic that you would use for a young psychotic patient. When feasible, start low and titrate to effect.

Acknowledgement: Thanks to Dr. Casey Albin (@caseyalbin) for thoughtful comments on this chapter.

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