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Updated: May 6th 2021

Antipsychotic Toxicity and Poisoning

Author

Amberly R. Johnson, PharmD

Section Editors

Mike Darracq, MD, MPH

Michael Moss, MD

Joshua Nogar, MD

Associate Editor

Sean Nordt, MD, PharmD

Editors in Chief

Amal Mattu, MD

Stuart Swadron, MD

Sean Patrick Nordt, MD, PharmD

Whitney Johnson, MD, MS

Rapid Access
Approach to the Critical Patient
Antipsychotic toxicity commonly results in central nervous
system (CNS) and cardiac disturbances.

AIRWAY/BREATHING

Intubation and ventilation may be required in cases of

severe CNS depression.

CIRCULATION

Hypotension should be managed with IV crystalloids.

The addition of vasoactive medications for refractory
hypotension is uncommon; if required, other etiologies
for shock should be considered.

Dysrhythmias

QRS widening (>100 ms) or R wave amplitude in aVR

(>3 mm)

Sodium bicarbonate 8.4% 1-2 mEq/kg IV bolus,

repeat dose until QRS narrows; consider infusion
150 mEq (3 amps in 1 L 5% dextrose in water) at 2x
maintenance rate.

QTc prolongation (>500 ms)

Magnesium 2 g IV

Optimize potassium

Torsades de pointes

Dopamine 10 μg/kg/min or Isoproterenol infusion 2-10

μg/min, titrate to heart rate >100 bpm

Overdrive pacing
 DISABILITY

Neuroleptic malignant syndrome

Discontinue all antipsychotic medications.

Active cooling (fluids, ice, cooling blanket),

temperature monitoring.

Muscle rigidity should be aggressively treated with

benzodiazepines.

Adjunct therapy (consultation with toxicologist/poison

control center).

Bromocriptine 2.5 mg orally (PO) q6-8h titrated to

maximum of 40 mg per d

Dantrolene 2.5 mg/kg IV q5-15 min, with a maximum

cumulative dose of 10 mg/kg (used with variable
efficacy, but not Food and Drug Administration-
approved for neuroleptic malignant syndrome).

EM:RAP Link
Antipsychotics & Antiemetics audio

Key Concepts
Antipsychotics are frequently divided into first-generation or
“typical” agents (eg, chlorpromazine, haloperidol, thioridazine),
and second-generation or “atypical” agents (eg, quetiapine,
risperidone, clozapine).

The most common toxic antipsychotic effects include: CNS

depression, tachycardia, hypotension, extrapyramidal
symptoms, and QTc prolongation.
 Extrapyramidal symptoms occur more frequently with first-
generation antipsychotics than with second-generation
antipsychotics.

The majority of antipsychotic exposures are intentional and

commonly involve co-ingestants.

PEARLS

Antipsychotic medication overdose in isolation rarely

produces hemodynamic collapse or severe complications.

Neuroleptic malignant syndrome is a rare, life-threatening

syndrome associated with hyperthermia, lead pipe rigidity,
altered mental status, and autonomic instability in conjunction
with antipsychotic use in the prior 72 h. Neuroleptic malignant
syndrome may be confused with dystonia and/or serotonin
toxicity.

Diagnosis
Textbook presentation
An adult female was found down and brought to the ED by
emergency medical services. She is responsive only to painful
stimuli (Glasgow coma score 8). Vital signs are significant for
tachycardia (heart rate: 130 beats/min) and mild hypotension
(systolic blood pressure: 90 mm Hg); her fingerstick glucose is
129, and ECG reveals QTc prolongation (QTc: 510 ms). An empty
bottle of quetiapine was found in her pocket.

The onset of antipsychotic toxic effects is related to the peak

and the duration of action of the medication.

In general, dystonic reactions are more common with first-

generation antipsychotics, and hypotension is more common
with second-generation antipsychotics.
 Neuroleptic malignant syndrome is quite rare, occurring in
0.01%-0.02% of patients treated with antipsychotics. However,
there is an increased risk for neuroleptic malignant syndrome
with the use of a first-generation antipsychotic.

Diagnostic testing
No diagnostic imaging is warranted unless there is concern for
an alternate etiology of CNS depression and altered mental
status.

Obtaining the following labs for analysis is recommended:

blood gas, comprehensive metabolic panel, complete blood
count, and creatine kinase.

In the setting of an intentional ingestion, further toxicology

screening is also important, consider obtaining acetaminophen,
salicylate, and ethanol concentrations.

Treatment
Antipsychotic overdose in isolation is rarely life-threatening.

The mainstay in any acute poisoning is a thorough assessment

with contemporaneous patient stabilization, resuscitation, and
supportive care.

Airway, breathing, and circulation must be optimized via

continuous monitoring (eg, airway patency/protection,
dysrhythmias, hypotension) and frequent reassessment of the
patient.

Intubation, IV crystalloids, and other specific therapies (eg,

sodium bicarbonate for dysrhythmias) may be indicated in
select patients (See Approach to the Critical Patient).

Gastrointestinal decontamination with oral activated charcoal 1

g/kg may be considered if given within 1-2 h of the ingestion
 event. The patient must also be alert and cooperative, which is
unlikely given the sedative effects of antipsychotics.

Dystonia can be managed with either of the following agents:

Diphenhydramine

50 mg intramuscular (IM)/IV/PO in adults

0.5-1 mg/kg IV/IM/PO (max 50 mg per dose) in pediatric

patients

Benztropine

1-2 mg IV/IM/PO q8-12h in adults

1-4 mg IV/IM/PO q12-24h for pediatric patients (>3 y of age)

exhibiting a severe reaction

Benzodiazepines can be used as an adjunct for dystonic

reaction. They are also first-line in the event of a seizure;
although seizures are rare with antipsychotic toxicity.

Lorazepam 1-2 mg IV (0.05-0.1 mg/kg IV in pediatric patients)

Adults are frequently under-dosed; give appropriate

weight-based dose.

Repeat 0.1 mg/kg within 5-10 min if the seizure does not
terminate.

Diazepam 5-10 mg IV diazepam (0.1-0.3 mg/kg IV pediatrics)

Double the dose within 5-10 min if the seizure does not
terminate.

Disposition
Consultations
 Toxicologist or Poison Control Center (800) 222-1222
(throughout the United States)

Psychiatry (for any intentional overdose)

Home
Patients who are asymptomatic (normalization of mentation,
vital signs, and ECG) after >6 h of observation in a monitored
unit can safely be discharged home.

Admission
Intensive/Intermediate Care Unit

Intubated/sedated

CNS toxicity

Agitation, delirium, coma, seizures

Cardiac toxicity

Tachycardia, hypotension, dysrhythmias

Neuroleptic malignant syndrome or suspected neuroleptic

malignant syndrome

Deep Dive
Background
Antipsychotics table are structurally diverse agents that are
available through various routes of administration.

Antipsychotics are Food and Drug Administration-approved for

the management of schizophrenia and bipolar disorder. Other
 specific indications include the treatment of nausea and
vomiting (droperidol, chlorpromazine, prochlorperazine, and
perphenazine), Tourette’s disorder (haloperidol and pimozide),
irritability associated with autistic disorder (risperidone), and
intractable hiccups (chlorpromazine).

The therapeutic use of first-generation antipsychotics has

largely been replaced by the use of second-generation
antipsychotics due to the decreased incidence of
extrapyramidal symptoms in patients taking second-generation
antipsychotics.

Epidemiology
In 2018, 49,344 antipsychotic exposures were reported to
United States poison control centers. The majority of these
exposures were intentional (61%) and in patients >20 y of age
(64%). Most exposures were to second-generation
antipsychotics (92%) and involved coingestants (61%). Moderate
effects occurred in 4,879 exposures and major effects occurred
in 699 exposures. Eleven antipsychotic-related fatalities
occurred, with the majority (82%) involving second-generation
antipsychotics.

In a review of exposures reported to United States poison

control centers from 2000 to 2014, olanzapine, quetiapine, and
ziprasidone were associated with higher mortality rates (6.1, 7.6,
and 5.6 per 10,000 exposures, respectively) compared with
other second-generation antipsychotics, aripiprazole,
lurasidone, and risperidone. Olanzapine and quetiapine were
associated with higher morbidity rates (235.4 and 238.5 per
1,000 exposures, respectively) than aripiprazole, lurasidone,
risperidone, and ziprasidone.

Pathophysiology
 Antipsychotics antagonize dopamine, serotonin, adrenergic,
muscarinic, and histamine receptors at varying degrees, which
causes their therapeutic and toxic effects. In addition,
antipsychotics block potassium channels and, to a lesser extent,
sodium channels.

First-generation antipsychotics are primarily dopamine D2

receptor antagonists.

Haloperidol, fluphenazine, and pimozide have higher binding

affinities for the D2 receptor and are considered high-potency
dopamine antagonists. Occupancy rates of the D2 receptor
>60% are needed for medication to be an effective
antipsychotic. Drugs with D2 receptor occupancy rates >80%
are more frequently associated with extrapyramidal symptoms.

Second-generation antipsychotics are potent antagonists of

serotonin 5HT2A receptors and less potent antagonists of
dopamine receptors.

Muscarinic antagonism is responsible for the anticholinergic

effects (eg, tachycardia, delirium).

Hypotension occurs due to adrenergic antagonist effects at

alpha receptors.

Antagonism of histamine H1 receptors is responsible for

sedative effects.

Potassium and sodium channel blockade is responsible for

conduction disturbances, QTc prolongation, and QRS widening.

Diagnostic Considerations
The classic signs and symptoms of antipsychotic ingestion
include CNS depression, tachycardia, QTc prolongation,
hypotension, and dystonia.
CNS depression was more common with second-generation
than with first-generation antipsychotics (odds ratio 2.18, 95%
confidence interval: 1.30-3.65) in a review of antipsychotic
exposures reported to the California Poison Control System.
United States poison control center data from 2000 to 2014
revealed that coma was most frequently reported for
olanzapine alone (17.35%), olanzapine in combination with
fluoxetine (16.5%), quetiapine (12.81%), and perphenazine in
combination with amitriptyline (25.58%).

Similar to CNS depression, respiratory depression was more

common with second-generation antipsychotic ingestion than
with first-generation antipsychotic ingestion (odds ratio 2.39,
95% confidence interval: 1.09-5.26) in a review of antipsychotic
exposures reported to the California Poison Control System.
United States poison control center data from 2000 to 2014
revealed that respiratory depression was most frequently
reported for olanzapine alone (7.59%), olanzapine in
combination with fluoxetine (8.74%), quetiapine (7.99%), and
perphenazine in combination with amitriptyline (10.47%).

Tachycardia and hypotension are the most common vital sign

abnormalities reported with antipsychotic ingestion. In a
review of antipsychotic exposures reported to the California
Poison Control System, hypotension was more common with
second-generation antipsychotic ingestion than with first-
generation antipsychotics (odds ratio 1.8, 95% confidence
interval: 1.23-2.63). Antipsychotics with the highest rates of
hypotension in this study were quetiapine (17.6%), risperidone
(13.2%), thioridazine (12.2%), chlorpromazine (8.6%), haloperidol
(8.1%), and olanzapine (6.3%).

QTc prolongation has been reported with both first-generation

and second-generation antipsychotic ingestion in systematic
reviews and to poison control centers. Thioridazine and
haloperidol are first-generation antipsychotics with high rates of
QTc prolongation. Quetiapine, risperidone, and ziprasidone
have higher rates of QTc prolongation than other second-
generation antipsychotics.

QRS-complex widening is reported less frequently than QTc

prolongation and is mainly observed with thioridazine and
quetiapine. If severe, consider the possibility of coingestants
(eg, tricyclic antidepressants).

Dysrhythmias, including torsades de pointes, are rare but have

been reported most commonly with the ingestion of
thioridazine, haloperidol, and amisulpride (a non-United States
drug).

Extrapyramidal symptoms include acute dystonia, akathisia,

Parkinsonism, tardive dyskinesia, and neuroleptic malignant
syndrome. Dystonic reactions were less common with second-
generation than with first-generation antipsychotics (odds ratio
0.12, 95% confidence interval: 0.08-0.19) in a review of
antipsychotic exposures reported to the California Poison
Control System. In this study, antipsychotics with the highest
rate of dystonic reaction were haloperidol (39 cases, 39.4%) and
risperidone (19 cases, 8.6%).

Seizures were rare (second-generation antipsychotic 1.9% vs.

first-generation antipsychotic 1%) in a review of antipsychotic
exposures reported to the California Poison Control System.
However, clozapine at high therapeutic doses and in overdose
is associated with seizures.

Neuroleptic malignant syndrome has a mortality rate of 5.6%.

Its onset is slower than that of serotonin toxicity, with most
cases occurring after 1 wk of antipsychotic use. In contrast to
serotonin toxicity, neuroleptic malignant syndrome does not
cause hyperreflexia or clonus. Neuroleptic malignant syndrome
is most often associated with therapeutic use and dose
changes for high-potency antipsychotics rather than overdose.
Neurologic changes associated with neuroleptic malignant
syndrome generally occur before systemic signs and
symptoms. Agitation, exhaustion, dehydration, and iron
deficiency have been associated with an increased risk of
neuroleptic malignant syndrome. High-potency first-generation
antipsychotics such as haloperidol and fluphenazine, parenteral
administration, rapid titration rates, higher total drug dosages,
and polypharmacy are drug-related risk factors for neuroleptic
malignant syndrome.

Radiographic evaluations are not helpful in the diagnosis of

antipsychotic toxicity. Computed tomography of the head may
be useful in ruling out other causes of CNS depression and
altered mental status.

Specific antipsychotic concentrations are not readily available in

the ED and thus are not helpful in the acute management of
toxic ingestions.

Cross reactivity with serum and urine tricyclic antidepressant

screens has been reported with antipsychotics that have three-
ringed structures, such as quetiapine.

The majority of antipsychotic exposures reported to United

States poison control centers involve coingestants (61%).
Consider serum acetaminophen, salicylate, and ethanol levels
in addition to any other potentially toxic medications that are
prescribed to the patient (eg, lithium, valproic acid) to rule out
potential coingestants.

Agranulocytosis can occur with the therapeutic use of

clozapine. Patients are required to enroll in the Clozapine Risk
Evaluation and Mitigation Strategies program and have routine
blood testing performed before receipt of their clozapine
prescriptions.
Therapeutic Considerations
According to United States poison control centers, 14,547
antipsychotic exposures occurred in a managed health care
facility in 2018. Treatment is primarily symptomatic and
supportive.

The rates of intubation secondary to antipsychotic ingestion are

reported to be between 5.8 and 7.4%. In a review of patients
managed at the bedside from 2010 to 2014, 158 antipsychotic
ingestions (first-generation and second-generation) were
managed with intubation, with the majority of cases related to
quetiapine ingestion (70.9%). In a review of United States
poison control center data from 2000 to 2013, Second-
generation antipsychotics were the most common single
substance exposure managed with intubation.

Both potassium and magnesium supplementation (at the higher

end of the normal range) is recommended in patients with QTc
prolongation. Torsade de pointes has been reported but is rare.

Bromocriptine and dantrolene have been used for the

treatment of neuroleptic malignant syndrome. Bromocriptine is
a dopamine agonist, available in oral form only, and is not
expected to rapidly reverse the signs or symptoms of
neuroleptic malignant syndrome. Dantrolene is the antidote for
malignant hyperthermia, but has been used for severe
neuroleptic malignant syndrome with mixed efficacy.

IV fat emulsion has been used in the treatment of antipsychotic

ingestion, and systematic reviews show that the quality of
evidence supporting its use is low. Consult with a toxicologist
or poison control center prior to considering IV lipid emulsion
for an antipsychotic ingestion.

Prevention
 Suicidal patients should undergo psychiatric evaluation once
they have been medically cleared.

Prescribing antipsychotics with more favorable toxicity profiles

may prevent morbidity and mortality related to overdose.

Additional Information
Suggested EM:RAP Link
Dystonic Reaction emrap-video

References show