First-generation (typical) antipsychotic medication poisoning

INTRODUCTION — 

Antipsychotic medications are primarily used to treat agitation, hallucinations, and other manifestations of psychosis arising from numerous causes, including psychiatric illnesses (schizophrenia, mania), medical illnesses (alcohol withdrawal), and neurologic disease (Alzheimer disease). When used to treat psychiatric diseases, they also aid in restructuring disordered thinking. Although their use in psychiatric disorders has been outpaced by that of atypical antipsychotic agents, they remain widely used to treat a number of nonpsychiatric conditions, including nausea and vomiting (prochlorperazine, promethazine, droperidol), vertigo (prochlorperazine, droperidol), itching (promethazine), migraine headache (prochlorperazine, haloperidol, droperidol), Tourette's syndrome (haloperidol, pimozide), postherpetic neuralgia (fluphenazine), and hiccups (chlorpromazine).

This topic review will discuss the management of typical (ie, first generation) high and low potency antipsychotic medication poisoning (table 1). A summary table to facilitate emergency management is provided (table 2). A general approach to the poisoned patient and poisoning from atypical antipsychotic agents are discussed separately.

●(See "General approach to drug poisoning in adults".)

●(See "Approach to the child with occult toxic exposure".)

●(See "Initial management of the critically ill adult with an unknown overdose".)

●(See "Second-generation (atypical) antipsychotic medication poisoning".)

EPIDEMIOLOGY — 

The US Centers for Disease Control estimates that approximately 5800 patients are treated in United States emergency departments annually for adverse effects from typical antipsychotic medication, including unintentional overdose, a rate of 26 ED visits per 10,000 outpatient prescription visits [1]. Haloperidol was responsible for a higher rate of ED visits (43.3 per 10,000 outpatient prescription visits) than any other psychiatric medication. In 2022, America’s poison centers reported approximately 2000 exposures to phenothiazines, resulting in no deaths; one death was attributed to clozapine overdose [2].

PHARMACOLOGY AND CELLULAR TOXICOLOGY — 

Antipsychotic medications are commonly categorized as "low potency," "high potency," or "atypical" agents, though these distinctions may not be as clear as commonly perceived [3]. The typical antipsychotic agents antagonize dopamine (D) receptors in several areas of the brain, including the cortex, basal ganglia, limbic system, hypothalamus, and chemoreceptor trigger zone. The efficacy and potency of these agents is directly related to D2 receptor binding affinity [4,5]. However, not all forms of D2 receptor blockade are desirable. D2 antagonism in the mesocortical regions impairs cognition and exacerbates the negative symptoms of schizophrenia, such as avolition, anhedonia, poverty of speech, flattened affect, and social withdrawal.

The typical antipsychotic agents also block a variety of other central and peripheral nervous system receptors. Blockade of muscarinic acetylcholine receptors may cause dry mouth, tachycardia, sedation, and constipation, and can provoke episodes of urinary retention and angle-closure glaucoma [4]. Alpha-1 adrenergic receptor antagonism can cause orthostatic hypotension and reflex tachycardia. Histamine-1 receptor antagonism contributes to sedation.

Antipsychotic agents can affect cardiac ion channels. Most typical antipsychotics block the KCNH2-encoded voltage-gated potassium channel (ie, hERG), reducing the delayed inward potassium rectifier (IKr) current and prolonging cardiac repolarization [6]. This is manifest on the electrocardiogram as QT interval prolongation, and, in extreme cases, this can lead to torsades de pointes (TdP) [7-12]. Although this effect is most pronounced with thioridazine, many other first-generation antipsychotic agents, including haloperidol, droperidol, pimozide, chlorpromazine, promethazine, and sertindole, have been associated with QT prolongation and TdP [13-16]. TdP risk has been well-documented in the absence of potassium channel binding, suggesting that other mechanisms may contribute to this syndrome [17]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

QRS prolongation may occur due to antipsychotic medication-induced sodium channel blockade, particularly with thioridazine and mesoridazine [6,18-20]. Several antipsychotic medications, including pimozide and haloperidol, block L-type calcium channels, but the relevance of this for human exposures is unclear [21].

Acute extrapyramidal syndromes (EPS), such as acute dystonic reactions and akathisia, appear to be related to an imbalance between dopamine (presumably D2) receptor antagonism and muscarinic (presumably M1) receptor antagonism in the central nervous system (CNS). Medications such as haloperidol and prochlorperazine, which have a high D2/M1 receptor affinity ratio, are the most likely to cause EPS. Subsequent research suggests that the kinetics of D2 receptor binding may be more important than overall binding affinity, and that serotonin 2A receptor occupancy may be protective [22,23]. M1 receptor antagonists, such as diphenhydramine and benztropine, and the dopamine agonist amantadine are equally effective remedies for acute EPS [24].

Although the neuroleptic malignant syndrome (NMS) has long been thought to be a centrally mediated phenomenon, some evidence suggests that antipsychotic medications directly affect skeletal muscle mitochondria, possibly uncoupling oxidative phosphorylation [25-27]. (See "Neuroleptic malignant syndrome".)

Antipsychotic medications are associated with an increased risk of sudden cardiac death, including cardiac arrest with pulseless electrical activity (PEA), and with venous thromboembolic disease [28-30]. It is unclear whether this is a result of the medications themselves or the disease being treated [31,32]. Antipsychotic medication use is associated with an increase in seizure frequency, compared with non-use [33]. Rare cases of rhabdomyolysis and massive asymptomatic creatine kinase elevation (MACKE) without rhabdomyolysis have been reported [34,35].

KINETICS — 

Typical antipsychotic medications are absorbed quickly and enter the brain rapidly. As an example, the peak clinical effect of orally administered prochlorperazine occurs within two to four hours after dosing [36]. In overdose, delayed peak serum concentrations can occur, particularly if anticholinergic effects delay gut motility.

Once absorbed, antipsychotic medications diffuse into lipophilic tissues; volumes of distribution (VD) are generally in the range of 8 to 10 L/kg, precluding removal by hemodialysis. Elimination half-lives range from 6 to 24 hours; for each agent, the range of half-lives measured varies greatly among individuals (table 3) [37].

CLINICAL FEATURES OF OVERDOSE

History — Great variability exists in the amount of drug needed to cause signs and symptoms of overdose. In general, the elderly and people who are naïve to the medications become symptomatic at lower doses. While conscious patients may give a history of overdose, many patients present obtunded and any history is provided by family, friends, first responders, pharmacists, and medical records review. Not all patients with antipsychotic medication overdose have a history of psychiatric illness; patients may overdose on medications obtained from family members or others.

Acute extrapyramidal syndromes (EPS), such as akathisia and dystonic reactions, can occur with antipsychotic medication at any dose. The time to onset varies widely. In one emergency department case series, 44 percent of patients who received intravenous prochlorperazine for migraine headache developed akathisia within one hour of administration, while an additional 3 percent developed akathisia within 48 hours [38]. The incidence of EPS from oral haloperidol dosing may be as high as 57 percent [39]. The onset of EPS appears to be more gradual following oral dosing: half of cases occur within 48 hours of initiation of the antipsychotic medication, and 90 percent occur within five days [40]. Extrapyramidal symptoms are rare in overdose.

Physical examination — Typical antipsychotic poisoning does not cause any pathognomonic signs. Pupils may be miotic, normal size, or mydriatic. Portions of the anticholinergic toxidrome, such as tachycardia, mild hyperthermia, dry skin, and diminished bowel sounds may be present, but this is by no means consistent or reliable. Mild hypotension may result from alpha adrenergic blockade. Profound hyperthermia suggests the neuroleptic malignant syndrome (NMS). Alterations in mental status range from mild somnolence to coma.

Akathisia is an acute psychomotor restlessness, characterized by a feeling of unease and inability to sit still. Most patients can suppress these behaviors briefly using voluntary control. Acute dystonic reactions are sustained muscular spasms, most commonly affecting the neck (30 percent), tongue (17 percent), or jaw (15 percent) [40]. Choreoathetoid movements, opisthotonus, oculogyric crisis, and respiratory dystonia are less common manifestations.

DIFFERENTIAL DIAGNOSIS — 

Patients who have overdosed on antipsychotic medication may be clinically indistinguishable from those who have overdosed on a wide variety of medications with sedative properties, including benzodiazepines, prescription insomnia medications (eg, zolpidem or zaleplon), cyclic antidepressants, skeletal muscle relaxants (eg, baclofen), centrally acting alpha 2 receptor agonists (eg, clonidine), anticonvulsants (eg, carbamazepine), and atypical antipsychotics. (See "Tricyclic antidepressant poisoning" and "Second-generation (atypical) antipsychotic medication poisoning" and "Phenytoin poisoning".)

Neither vital signs, physical examination, nor clinical course clearly distinguish cases of typical antipsychotic medication overdose from those of other sedatives. Fortunately, in the absence of cardiovascular effects, the same supportive care measures provide effective treatment for both typical antipsychotic medication overdoses and these mimics.

Many nontoxicologic syndromes can produce central nervous system (CNS) depression, including hypoglycemia, acute liver failure, CNS infections, massive cerebrovascular accidents, severe electrolyte disorders, blunt head trauma, and septic or other forms of shock (table 4). (See "Diagnosis of delirium and confusional states" and "Stupor and coma in adults".)

Because they cause anxiety and can be temporarily suppressed by reassurance and voluntary control, acute extrapyramidal syndromes are sometimes misdiagnosed as an anxiety reaction or functional neurological symptom disorder (conversion disorder).

ANCILLARY TESTING — 

No specific laboratory tests are needed to diagnose or treat typical antipsychotic medication overdose. Serum concentrations of specific antipsychotic drugs may be obtained if the diagnosis is in doubt. However, the results have little clinical value because they cannot be obtained readily and concentrations correlate poorly with clinical manifestations. Antipsychotic medications have been associated with hyponatremia and thus a serum sodium concentration should be measured in patients with an altered mental status or seizures [41]. Patients who develop hypotension, rhabdomyolysis, prolonged urinary retention, or neuroleptic malignant syndrome are at risk for acute kidney injury [42]. In such cases, serial measurements of creatinine and, in some cases, creatine kinase are appropriate.

Routine laboratory evaluation of the poisoned patient includes the following:

●Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status

●Basic metabolic profile (electrolytes, kidney function, and glucose) to evaluate for metabolic acidosis or acute kidney injury

●Acetaminophen and salicylate concentrations, to rule out these common coingestions

●Electrocardiogram (ECG), to rule out conduction system poisoning by drugs that effect the QRS or QTc intervals

●Pregnancy test in women of childbearing age

MANAGEMENT

Airway, breathing, and circulation — Although pure antipsychotic medication overdoses rarely cause significant respiratory depression, many patients overdose on multiple substances and require airway protection. Oxygen saturation monitoring should be performed and supplemental oxygen administered as necessary. (See "Rapid sequence intubation in adults for emergency medicine and critical care".)

Hypotension should initially be treated with intravenous (IV) boluses of isotonic fluid, such as normal saline or lactated Ringer solution. Hypotension refractory to IV fluids should be treated with a direct-acting alpha-adrenergic agonist, such as phenylephrine or norepinephrine.

QRS prolongation may contribute to impaired circulation. As with cyclic antidepressants, QRS prolongation from acute antipsychotic intoxication is treated with sodium bicarbonate, 1 to 2 mEq/kg IV push. Treatment of QRS prolongation with sodium bicarbonate is discussed separately. (See "Tricyclic antidepressant poisoning".)

A summary table to facilitate emergency management of typical antipsychotic medication poisoning is provided (table 2). The general management of drug poisoning is reviewed elsewhere. (See "General approach to drug poisoning in adults".)

General treatment and antidotal therapy — Most patients with antipsychotic medication overdose present with central nervous system (CNS) depression and no more than minor vital sign perturbations. These cases are easily managed with supportive care and hospitalization until signs of overdose have resolved.

Rarely, patients experience a severely symptomatic overdose. Patients with a profoundly depressed mental status or coma require aggressive intervention, including endotracheal intubation.

Seizures that occur in the setting of antipsychotic overdose or toxicity are treated with benzodiazepines. Such seizures are generally self-limited and traditional antiepileptics such as phenytoin are NOT indicated.

Hyperthermia, when mild, may be treated by undressing the patient or with evaporative cooling measures. Severe hyperthermia, particularly if it develops in the setting of muscular rigidity, altered mental status, and autonomic instability, raises the specter of neuroleptic malignant syndrome, and should be managed aggressively. (See "Nonexertional (classic) heat stroke in adults" and "Neuroleptic malignant syndrome".)

In patients who present with CNS depression, miosis, and an uncertain history, a trial administration of a mu-opioid receptor antagonist (eg, naloxone) is warranted to exclude the possibility of opioid overdose [43]. Naloxone does not reverse the CNS depression caused by antipsychotic medication overdosage. The use and dosing of naloxone are discussed separately. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy' and "Opioid intoxication in children and adolescents", section on 'Naloxone'.)

The benzodiazepine antidote flumazenil is not effective for treating antipsychotic medication overdose. Flumazenil should not be routinely administered to the patient with an unknown overdose. (See "Benzodiazepine poisoning", section on 'Role of antidote (flumazenil)'.)

GI decontamination — Antipsychotic medication overdose does not permanently injure any organ. If hypoxia and aspiration pneumonitis can be prevented, patients generally do well. No study has shown that gastrointestinal (GI) decontamination with activated charcoal (AC) improves the outcome or hastens the recovery from antipsychotic overdose. Therefore, we do not recommend GI decontamination. (See "Gastrointestinal decontamination of the poisoned patient".)

Acute extrapyramidal syndromes — Acute extrapyramidal syndromes (EPS), such as dystonic reactions and akathisia, are treated with diphenhydramine (25 to 50 mg IV in adults; 0.5 to 1 mg/kg in children). Benztropine (1 to 2 mg IV in adults; 0.05 mg/kg in children over three years old with severe reaction) may be used initially, or if diphenhydramine therapy fails. Response is often dramatic and typically occurs within minutes of intravenous drug administration. Although the IV route is preferred, both diphenhydramine and benztropine may be given IM or orally. If initial treatment is successful, therapy is continued orally for two to three days to prevent recurrence.

Alternative treatments for EPS include benzodiazepines (eg, lorazepam 1 to 2 mg IV in adults; 0.05 mg/kg IV in children), amantadine (100 mg orally twice or three times daily in adults), or biperiden (2 mg orally in adults). At least two controlled studies have shown amantadine to be as effective as anticholinergic therapy, with fewer side effects [24,44]. Propranolol (20 to 40 mg initial dose) reduces involuntary movements in akathisia, but does not reduce anxiety [45]. A randomized trial of 13 patients with acute akathisia from antipsychotic medications reported a benefit from trazodone (100 mg/day orally in adults) [46].

QT interval prolongation — Although many typical antipsychotic medications prolong the QT interval, torsades de pointes (TdP) is uncommon. Management of QT prolongation consists of cardiac monitoring and correction of electrolyte disorders, particularly hypokalemia and hypomagnesemia. Intravenous potassium infusion was found to correct drug related QT prolongation in an observational study of 12 subjects [47]. However, prophylactic administration of potassium to patients without hypokalemia is not advised. (See "Clinical manifestations and treatment of hypokalemia in adults".)

Should polymorphic ventricular tachycardia (VT) occur, it can be treated with magnesium sulfate (1 to 2 g IV), overdrive pacing, isoproterenol infusion, or synchronized or unsynchronized cardioversion. Stopping any offending medication, including antipsychotic medications that prolong the QT interval, is paramount. Because up to 10 percent of patients who develop medication-related TdP harbor mutations associated with the long QT syndrome, these patients should be referred to a cardiologist. The management of polymorphic VT is discussed elsewhere. (See "Overview of the acute management of tachyarrhythmias", section on 'Polymorphic ventricular tachycardia' and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)

It is important to avoid giving medications that would further prolong repolarization to the patient with a prolonged QT interval. A list of such drugs can be found in the following table (table 5) and at QTDrugs Lists. In addition to antipsychotics and antidepressants, common medications on this list include amiodarone, clarithromycin, erythromycin, methadone, ondansetron, and pentamidine [16].

Studies involving patients with the genetically determined congenital long-QT syndrome suggest that prolongation of the absolute (uncorrected) QT interval beyond 500 msec confers an increased risk of TdP. Unfortunately, data correlating the QT interval (absolute or corrected) with the risk of drug induced TdP are lacking, and some evidence is contradictory. A reasonable, conservative approach is to continue monitoring a patient until the heart rate and QTc are no longer in the "at-risk" area of the QT Interval Nomogram, which can be found in the following reference available online [48], or until the Bazett's corrected QTc interval is less than 500 msec and decreasing (calculator 1).

Anticholinergic delirium — All typical antipsychotic medications have anticholinergic (antimuscarinic) properties; overdoses of typical antipsychotic medications occasionally present with anticholinergic delirium. Physostigmine (adults: 1 to 2 mg IV over 2 minutes; children: 0.02 to 0.5 mg over 2 minutes) can be used to temporarily reverse altered mental status from anticholinergic delirium [49]. During shortages of physostigmine, rivastigmine (oral or transdermal) has been a successful alternative [50,51]. The management of anticholinergic delirium and related symptoms is discussed further elsewhere. (See "Anticholinergic poisoning".)

Neuroleptic malignant syndrome — Neuroleptic malignant syndrome (NMS) is an uncommon but potentially lethal side effect of antipsychotic medications characterized by mental status change, rigidity, fever, and dysautonomia (eg, labile blood pressure). The management of NMS is discussed elsewhere. (See "Neuroleptic malignant syndrome", section on 'Management'.)

A related condition, malignant catatonia, has been described. Malignant catatonia resembles NMS, but without fever, and usually responds to benzodiazepines. (See "Catatonia in adults: Epidemiology, clinical features, assessment, and diagnosis", section on 'Lorazepam challenge'.)

Extracorporeal removal — Because of their lipophilicity, high protein binding, and large volume of distribution, hemodialysis is not useful in the management of antipsychotic medication overdose.

Ongoing treatment and disposition — After initial stabilization, care of the patient with typical antipsychotic medication overdose is primarily supportive. Because the elimination half-life of these agents ranges from 6 to 24 hours and the antimuscarinic effects of the drugs can cause prolonged GI absorption, recovery generally takes one to three days. Although occasionally patients wake up quickly enough to be discharged from the emergency department (ED), hospital admission is typically necessary. Peak clinical effects are usually manifest upon or shortly after arrival to the hospital. Depending upon the nursing and monitoring resources available on inpatient units, patients who remain stable after a period of observation in the ED may not require ICU admission.

Although most patients who overdose on antipsychotic medications survive the episode, these patients remain at high risk of subsequent mortality due to repeat self-poisoning and violent suicide [52]. After medical stabilization, psychiatric assessment and care are of critical importance.

PEDIATRIC CONSIDERATIONS — 

The manifestations and management of typical antipsychotic medication overdose are the same in children and adults.

A child who accidentally ingests a dose of a typical antipsychotic medication that is less than the equivalent of the maximum therapeutic dose for a 24-hour period for that child's weight, has no sign of intoxication after a four- to six-hour period of observation, and has reliable caregivers may be observed at home rather than admitted to the hospital.

Consultation with a poison center is strongly recommended in all cases of pediatric overdose. (See 'Additional resources' below.)

ADDITIONAL RESOURCES

Regional poison centers — Regional poison centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment".)

SUMMARY AND RECOMMENDATIONS — 

A summary table to facilitate emergency management is provided (table 2).

●Pharmacology – The first-generation (typical) antipsychotic agents antagonize dopamine (D) receptors; the efficacy and potency of these agents is directly related to D2 receptor binding affinity. They also antagonize a variety of other nervous system receptors and ion channels including muscarinic acetylcholine receptors, alpha-1 adrenergic receptors, histamine-1 receptors, KCNH2-encoded potassium (ie, hERG) channels, and sodium channels. A table of common antipsychotic medications is provided (table 1). (See 'Pharmacology and cellular toxicology' above.)

●Obtaining history – Many patients present obtunded and history is obtained from family, friends, first responders, and pharmacists. (See 'History' above.)

●Clinical features of overdose – Typical antipsychotic poisoning does not cause any pathognomonic signs and great variability exists in the amount of typical antipsychotic medication needed to cause signs and symptoms. Most patients with isolated antipsychotic medication overdose present with central nervous system (CNS) depression and no more than minor vital sign perturbations. (See 'Clinical features of overdose' above.)

•Alterations in mental status range from mild somnolence to coma. Seizures can occur but are generally self-limited.

•Portions of the anticholinergic toxidrome, such as tachycardia, mild hyperthermia, dry skin, and diminished bowel sounds may be present. However, pupils may be miotic, normal size, or mydriatic.

•Cardiovascular effects can include mild hypotension, prolongation of the QRS interval, and prolongation of the QT interval (although torsades de pointes is uncommon).

•Profound hyperthermia suggests the neuroleptic malignant syndrome (NMS).

•Acute extrapyramidal syndromes (EPS), such as akathisia and dystonic reactions, can occur with any dose.

●Differential diagnosis – Patients who have overdosed on antipsychotic medication may be clinically indistinguishable from those who have overdosed on a wide variety of medications with sedative properties (eg, benzodiazepines, anticonvulsants, cyclic antidepressants, atypical antipsychotics), as well as patients with somnolence or delirium from medical causes (eg, hypoglycemia, CNS infection, head trauma). (See 'Differential diagnosis' above.)

●Ancillary testing – No specific laboratory tests are needed to diagnose or treat typical antipsychotic medication overdose. Serum concentrations of specific antipsychotic drugs may be obtained if the diagnosis is in doubt, but the results have little clinical value because they cannot be obtained readily and concentrations correlate poorly with clinical manifestations. Routine testing of the poisoned patient or suspected antipsychotic ingestion includes the following (see 'Ancillary testing' above):

•Fingerstick glucose

•Basic metabolic profile

•Acetaminophen and salicylate concentrations

•Creatine kinase (if concern for rhabdomyolysis or neuroleptic malignant syndrome)

•Electrocardiogram (ECG)

•Pregnancy test in female patients of childbearing age

●Management – A summary table to facilitate emergency management of typical antipsychotic medication poisoning is provided (table 2). Most cases are managed with supportive care alone. Some patients overdose on multiple substances and require airway protection. (See 'Management' above.)

•Hypotension is treated with intravenous (IV) boluses of isotonic fluid, and if refractory, should be treated with a direct-acting alpha-adrenergic agonist, such as phenylephrine or norepinephrine. (See 'Airway, breathing, and circulation' above.)

•QRS prolongation from acute antipsychotic intoxication is treated with sodium bicarbonate. (See 'Airway, breathing, and circulation' above and "Tricyclic antidepressant poisoning", section on 'Sodium bicarbonate for cardiac toxicity'.)

•Management of QT prolongation consists of cardiac monitoring and correction of electrolyte disorders, particularly hypokalemia and hypomagnesemia. (See 'QT interval prolongation' above.)

•EPS (eg, dystonic reactions, akathisia) are treated with diphenhydramine or benztropine. Response is often dramatic and typically occurs within minutes of IV drug administration. (See 'Acute extrapyramidal syndromes' above.)

•Seizures are treated with benzodiazepines. (See 'General treatment and antidotal therapy' above.)

•Severe hyperthermia, particularly if it develops in the setting of muscular rigidity, altered mental status, and autonomic instability, raises the specter of NMS, and should be managed aggressively. (See 'General treatment and antidotal therapy' above and "Neuroleptic malignant syndrome".)