Neuroleptic Agent Toxicity 

Updated: Oct 04, 2019
Author: Jay T Melton, MD; Chief Editor: Michael A Miller, MD 

Overview

Practice Essentials

Neuroleptic agents, also known as antipsychotics, can reduce confusion, delusions, hallucinations, and psychomotor agitation in psychotic patients. The terms neuroleptics and antipsychotics are used interchangeably throughout this article. The first-generation neuroleptic agents (typical antipsychotics), also known as major tranquilizers, comprise a group of several classes of drugs, which include butyrophenones, dibenzoxazepines, diphenylbutylpiperidine, phenothiazines, thioxanthenes. The U.S. Food and Drug Administration (FDA) approved typical (first-generation) antipsychotics and their indications are summarized in the table below.

Table 1. FDA-approved typical antipsychotic medications (Open Table in a new window)

Drug Indication
Droperidol (Dridol) Agitation
Haloperidol (Haldol)

Schizophrenia

Tourette syndrome

Hyperactivity

Severe childhood behavioral disorders

Loxapine (Loxitane) Schizophrenia
Pimozide Tourette syndrome
Thiothixene (Navane) Schizophrenia
Fluphenazine (Prolixin) Psychotic disorders
Perphenazine (Trilafon) Schizophrenia
Thioridazine (Mellaril) Schizophrenia
Trifluoperazine (Stelazine)

Schizophrenia

Generalized nonpsychotic anxiety

Chlorpromazine (Thorazine) Schizophrenia
Prochlorperazine (Compro)

Schizophrenia

Generalized nonpsychotic anxiety

Neuroleptics are also used as sedatives, tranquilizers, for their antiemetic properties, to control hiccups, and in the treatment of drug-induced psychosis. Any of the acute adverse effects of neuroleptics may occur in these settings.

Because of the consequential adverse effects of the major tranquilizers, second-generation, or atypical, antipsychotic agents, were introduced beginning in the 1970s with clozapine. The FDA-approved second-generation (atypical) antipsychotics and their indications are summarized in the table below.

Table 2. FDA-approved atypical antipsychotic medications (Open Table in a new window)

Drug Indications
Clozapine (Clozaril )

Treatment-resistant schizophrenia

Reduce the risk of suicidal behavior in younger patients with schizophrenia

Olanzapine (Zyprexa)

Schizophrenia 

Bipolar disorder 

Treatment resistant depression

Quetiapine (Seroquel)

Schizophrenia

Bipolar disorder 

Adjunctive therapy for major depressive disorder

Ziprasidone (Geodon)

Schizophrenia 

Bipolar disorder 

Aripiprazole (Abilify)

Schizophrenia

Bipolar disorder (manic/mixed) monotherapy or adjunctive to lithium or valproate

Adjunctive treatment of major depressive disorder

Irritability associated with autistic disorder

Acute treatment of agitation

Paliperidone (Invega)

Schizophrenia 

Schizoaffective disorder

Risperidone (Risperdal)

Schizophrenia 

Bipolar disorder 

Irritability associated with autistic disorder

Asenapine (Saphris)

Acute schizophrenia

Bipolar disorder type 1 (manic/mixed)

Iloperidone (Fanapt) Acute schizophrenia

Increasingly, atypical antipsychotics are being used for a growing range of indications such as major depression, anxiety, and insomnia.  Despite the widespread off-label use, only six atypical antipsychotics currently have FDA-approved indications for use in children and adolescents: aripiprazole, asenapine, olanzapine, paliperidone, quetiapine, and risperidone. Indications include schizophrenia, bipolar disorder, Tourette'syndrome and irritability associated with autistic disorder. No atypical antipsychotics are FDA approved for children younger than 6 years old.[1]

Controversy over the growing list of indications for these powerful drugs initially approved for schizophrenia and bipolar disorder stems from aggressive clinical trials by the drug makers as well as likely publication bias. Potential adverse effects of the atypical antipsychotic agents can be more harmful than those of the first-line treatment agents for these newer indications. Generally, all neuroleptic medications are capable of causing the following adverse effects:

  • Anticholinergic effects: Tachycardia; hyperthermia; urinary retention; ileus; mydriasis; toxic psychosis; dry mucous membranes; and hot, dry, flushed skin

  • Extrapyramidal symptoms[2] : Alteration in the normal balance between central acetylcholine and dopamine transmission can produce dystonia, oculogyric crisis, torticollis, acute parkinsonism, akathisia, and other movement disorders. Long-term use of major tranquilizers is associated with buccolingual movements (tardive dyskinesia), parkinsonism, and akathisia.

  • Neuroleptic malignant syndrome (NMS)[2] : All of the major tranquilizers have been implicated in the development of NMS, a life-threatening derangement that affects multiple organ systems and results in significant mortality. NMS is less common with atypical antipsychotic use. Hypothalamic D2 receptor blockade results in an elevated temperature set point and in the impairment of heat-dissipating mechanisms; it is also associated with blockade of striatal D2 receptors, which may result in muscle rigidity and hyperthermia.

  • Seizures: Most major tranquilizers lower the seizure threshold and can result in seizures at high doses and in susceptible individuals. With loxapine, seizures may be recurrent.

  • Cardiac effects: Prolongation of the QT interval and QRS complex can result in arrhythmias. QT prolongation in antipsychotic use is caused by potassium channel blockade. Sodium blockade causes prolongation of the QRS complex. This effect is mainly seen with thioridazine and mesoridazine.

  • Hypotension: Phenothiazines are potent alpha-adrenergic blockers that result in significant orthostatic hypotension, even in therapeutic doses for some patients. In overdose, hypotension may be severe.

  • Sedation

  • Respiratory depression: Hypoxia and aspiration of gastric contents can occur in children and in mixed overdoses.

  • Hypothermia: Certain major tranquilizers can prevent shivering, limiting the body's ability to generate heat.

  • Metabolic syndrome leading to weight gain, diabetes, and cardiovascular disease[3]

For discussion of toxicity of other neuroleptic agents, see Selective Serotonin Reuptake Inhibitor Toxicity and Lithium Toxicity.

 

Pathophysiology

The neuroleptics (major tranquilizers) or typical antipsychotics have complex central nervous system (CNS) actions that are incompletely defined. Their therapeutic action is thought to be primarily by antagonism of central dopaminergic (D2 receptor) neurotransmission, although they also have antagonist effects at muscarinic, serotonergic, alpha1-adrenergic, and H1-histaminergic receptors.

The newer atypical antipsychotics also have D2 receptor antagonism, and most have 5-HT2 receptor antagonism. Aripiprazole is a mixed agonist-antagonist at the serotonin and dopamine receptors; it is a partial D2 and 5-HT2(1A) agonist and a 5-HT(2A) receptor antagonist. These drugs are less likely to cause extrapyramidal adverse effects or a sustained elevated prolactin level, but they have further serious metabolic adverse effects associated with their use.

Table 3. Receptor Affinity (Antagonism) of Atypical Antipsychotics [4] (Open Table in a new window)

Drug

Dopamine D2

Serotonin 5-HT 2A

Muscarinic M1

Histamine H1

Alpha Adrenergic A-1

Aripiprazole

3+

3+

0

2+

2+

Clozapine

2+

3+

3+

3+

3+

Olanzapine

2+

3+

3+

2+

2+

Paliperidone

3+

3+

0

2+

3+

Quetiapine

1+

1+

3+

3+

3+

Risperidone

3+

3+

0

0

2+

Ziprasidone

3+

3+

0

0

3+

0 is no-to-minimal risk; 1+ is low risk; 2+ is moderate risk; 3+ is high risk.

Although all antipsychotic preparations share some toxic characteristics, the relative intensity of these effects varies greatly, depending on the individual drug and specific receptor affinity.

Etiology

All neuroleptic medications have the potential to cause adverse effects; however, certain combinations of medications (eg, lithium + haloperidol, anticholinergics + haloperidol), depot preparations (eg, fluphenazine and haloperidol), and stronger neuroleptics (eg, haloperidol) are more likely to produce adverse effects, including neuroleptic malignant syndrome (NMS).

A study of 6578 adult medical patients found a slightly increased risk of death within seven days of initiating haloperidol compared with initiating an atypical antipsychotic in patients with acute myocardial infarction. The absolute rate of death per 100 person-days was 1.7 for haloperidol (129 deaths) and 1.1 for atypical antipsychotics (92 deaths) during seven days of follow-up from treatment initiation. The association was strongest during the first four days of follow-up and decreased over time. By day 5, the increased risk was no longer evident (1.12; 95% confidence interval, 0.79 to 1.59).[5]

Epidemiology

Antipsychotics rank in the top 5 substance classes involved in human exposures. In 2017, the American Association of Poison Control Centers' Nationa Poison Data Systems (AAPCC-NPDS) reported that sedative/hypnotics/antipsychotics exposures as a class had the most rapid increase in exposures with more serious outcomes (4.91%/year) since 2000.[6] Overdose of antipsychotic medication is more common among psychiatric patients than other individuals, although unintentional ingestion by children is not uncommon. Antipsychotic medications are occasionally purchased illicitly by drug users, who may then develop adverse effects (eg, dystonia). 

In 2017, the AAPCC reported 17,121 single exposures to atypical antipsychotics. Of the 13,258 cases treated in a health care facility, no effects were reported in 2921 exposures; minor effects were seen in 5001 exposure, and moderate effects in 4192 exposures. Major effects were reported in 547 exposures and 9 deaths occurred.[6]  

Many formulations of major tranquilizers are used in Europe and are not available in the United States. Several of the atypical antipsychotics (ie, sertindole, amisulpride, bifeprunox) are not approved by the US Food and Drug Administration (FDA) for use in the United States.

No scientific data suggest any race-based difference in outcome of neuroleptic overdose or adverse drug effects. Some adverse effects of neuroleptic overdose are most common in males, while others are most common in females. For example, tardive dyskinesia is most common in older women, whereas neuroleptic malignant syndrome is most common in males.

An increased incidence of toxicity is seen in elderly persons.[7] This may be related to changes in metabolism or interactions due to the use of multiple other drugs. 

Prognosis

The outcome from an acute overdose of neuroleptic medication is usually favorable. The vast majority of patients with acute neuroleptic overdose recover completely. Parkinsonism, akathisia, and dystonias remit on discontinuation of the drug. However, prolonged periods of hypoxia, hyperthermia, status epilepticus, or hypotension may result in permanent neurologic or cardiac disability.  Poor outcomes are most often associated with small children, patients who develop NMS, and those who sustain dysrhythmias or prolonged hypotension. Permanent deficits occur in very few cases.  Tardive dyskinesia is the most frequently noted permanent disability related to prolonged use of neuroleptics.

Mortality is relatively rare with overdose of antipsychotic medication. However, if NMS occurs, the mortality rate can reach up to 10-12%. Risk factors for NMS include prior history of NMS, rapid initiation or change in drug dosing, and depot injections.

Toxicity of antipsychotic medications may be increased by co-ingestion of other agents, particularly drugs with similar metabolic pathways.[8]  It is not uncommon for patients to take multiple psychiatric medications (eg, lithium, cyclic or other antidepressants, benzodiazepines), and the combination of these medications in overdose often results in higher mortality rates. Polypharmacy also increases the prevalence of cardiovascular diseases and metabolic syndromes, such as weight gain and diabetes, further reducing the survival rate.[3]  

Although antipsychotic medications may have minimal morbidity and mortality in adults, ingestion of a single dose by a toddler may be lethal.

Long-term use of antipsychotic medications can lead to the development of extrapyramidal symptoms such as parkinsonism, hemiballismus, tardive dyskinesia, and prolonged QT interval.[9]  

Patient Education

Clinicians should explain and educate the patient and caretakers about possible adverse effects of antipsychotic medications. After an episode of neuroleptic malignant syndrome, educational approaches can help patients and their relatives understand what has happened to the patient, why the neuroleptic malignant syndrome has developed in the past, and the possibility of recurrence if antipsychotic therapy is restarted.

This education may help patients and their relatives to decide about giving consent to restart antipsychotics. If they give consent, they have to be aware of the early signs of neuroleptic malignant syndrome (eg, rigidity, hyperthermia, and changes of consciousness) and the importance of immediately seeking medical care if these arise.

In cases of accidental toddler ingestions, educate parents on how to childproof their homes from a toxicologic perspective.

For patient education information, see Drugs and Medications, Drug Overdose and Poisoning, and Child-Proofing Basics.

 

Presentation

History

The history is often unreliable or unavailable in intentional overdose. If patients are able to provide a history, they often can identify the type and dose of medication ingested; however, independently verify this information and consider other possible ingestions.

Patients with an acute overdose of major tranquilizers have a broad range of responses, depending on their degree of psychiatric derangement, age, habitual use of medications, and individual susceptibility to specific effects. Patients are usually somnolent, sedated, and hypoactive; however, actively psychotic patients may require massive doses of antipsychotics to control behavior before becoming sedated.

In massive overdose, the patient may be comatose and require intubation and respiratory support.

Patients ingesting antipsychotic medications, either short-term or long-term, often present to the emergency department with complaints of involuntary movement disorders. Hypotension and dysrhythmias may produce syncope, near syncope, orthostatic dizziness, and generalized weakness. Occasionally, patients present with a new-onset seizure or are discovered in a postictal state. Patients may present with dysrhythmia.

Phenothiazines and atypical antipsychotics (quetiapine and aripiprazole) are well known to cause prolongation of the QT interval on ECG and are associated with torsades de pointes. Other ECG findings include prolongation of the PR and QRS intervals and blocks. Tachycardia may result from the anticholinergic effects of these medications, or from alpha blockade and postural hypotension. Phenothiazines are associated with priapism caused by alpha blockade. Phenothiazines may cause photosensitivity, resulting in a blotchy red or purple discoloration of skin exposed to sunlight.

The diagnosis of neuroleptic malignant syndrome (NMS) is based on clinical features. Cardinal features are as follows[10] :

  • Severe muscular rigidity
  • Fever
  • Hyperthermia
  • Autonomic instability
  • Changes in the level of consciousness

Atypical NMS, without hyperthermia or muscle rigidity, has been reported in patients taking atypical antipsychotic drugs, such as aripiprazole. In one case report, fever, rigidity, and altered mental status were present for only a few hours.[11]

Physical Examination

Numerous physical findings are potentially associated with overdose of major tranquilizers, although some patients may remain relatively asymptomatic.[4]  Anticholinergic syndrome may manifest as toxic psychosis, agitation, confusion, mydriasis, urinary retention, ileus, hot flushed dry skin, and tachycardia. Patients may present with movement disorders.

Virtually all neuroleptics produce some degree of extrapyramidal dysfunction because of inhibition of dopaminergic transmission in the basal ganglia. Increased muscle tone, extrapyramidal symptoms, akathisia, restless legs, parkinsonism, or dystonia may occur. The following conditions may occur:

  • Acute dystonia
  • Parkinsonism
  • Acute akathisia
  • Tardive dyskinesia
  • Neuroleptic malignant syndrome (NMS)

Acute dystonia

A single therapeutic dose can result in involuntary muscle contraction of the eyes (oculogyric crisis), head, neck, and, less commonly, limbs, larynx, or pharynx. Symptom onset is usually delayed several hours.[12]  Laryngeal dystonia can result in asphyxiation and death.

Certain neuroleptics (eg, haloperidol, fluphenazine) are more potent inhibitors of dopamine in the basal ganglia and consequently cause more prominent symptoms. Patients present with torticollis, tongue protrusion or deviation, oculogyric crisis, opisthotonus, trismus, and gait disorders. This is more common in children (often after administration of neuroleptic antiemetics) and is self-limited. Response to anticholinergic medications is usually dramatic, although the condition may recur over the next several days.

Parkinsonism

Resulting from prolonged inhibition of basal ganglia D2 transmission, certain patients who take neuroleptics develop typical features of parkinsonism, including tremor, muscle rigidity, akinesia or bradykenisia.[12]  The condition is more common in elderly patients, in those with preexisting parkinsonism, and in females. It responds to anticholinergic medication.

Acute akathisia

Motor restlessness and the urge to move are dose related and occur in up to 20% of cases. This has also been implicated with rate of administration of these agents. A disorder associated with intravenous use of prochlorperazine as well as metoclopramide has been noted. Patients with this disorder become intensely anxious and restless and occasionally elope from the emergency department. These patients describe this acute dysphoric reaction as being very uncomfortable and creating the urge to crawl out of their skin. It may be distressing to a patient on antipsychotic medications, inducing violent behavior or suicidal ideation.[13]

Tardive dyskinesia

Tardive dyskinesia is a manifestation of chronic neuroleptic toxicity that is often permanent. It is characterized by involuntary repetitive movement of the lips and tongue (buccolingual dysplasia), limbs (choreoathetosis), and eyes (rapid blinking movements). Older women are most susceptible; however, it may occur in persons of any age after 24 months of therapy. All neuroleptics lower the seizure threshold to some degree, although certain ones (eg, chlorpromazine, clozapine, loxapine) have greater proconvulsant effects than others (eg, haloperidol, fluphenazine). The epileptogenic effect is dose-dependent, and the most common type of convulsion observed is a generalized tonic-clonic seizure.

A single therapeutic dose of a neuroleptic can result in involuntary muscle contraction of the face, neck, tongue, extraocular muscles, and, less commonly, of the limbs, larynx, or pharynx. The onset of symptoms is usually delayed several hours. Laryngeal dystonia can result in asphyxiation and death. The condition is more common in children (often after administration of neuroleptic antiemetics) and is self-limited. Response to anticholinergic medications is usually dramatic, although the condition may recur over the next several days.

After long-term use of these medications (> 24 mo), certain patients develop irreversible tardive dyskinesia that consists of characteristic involuntary movements of the face, lips, and tongue. Adverse effects associated with long-term neuroleptic use include galactorrhea (hyperprolactinemia), priapism, elevated liver function test results and cholestatic jaundice, skin photosensitivity, sexual dysfunction, and agranulocytosis (uniquely associated with use of clozapine).

Neuroleptic malignant syndrome

In NMS, physical findings may evolve over several days. Initial findings usually involve increased muscle tone, worsening extrapyramidal symptoms, and altered mental status. Diffuse lead-pipe muscle rigidity invariably occurs at some point during the course of illness. Persistent muscle contraction leads to rhabdomyolysis and, consequently, myoglobinuric renal failure. Creatinine kinase levels often are dramatically elevated (50-100% of cases). Muscle rigidity may be observed without NMS.

Hyperthermia commonly manifests as core temperature elevation from 101-108°F (38-42°) or higher. At the high range, acidosis results and essential enzymatic functions cease, resulting in multiorgan failure and possibly death. Hyperthermia may be observed in many patients who take neuroleptic medications without full-blown NMS. Patients with NMS are generally confused and disoriented and may become catatonic or comatose.

Other manifestations

Miscellaneous abnormalities include the following:

Withdrawal symptoms may result after discontinuation or dose changes. Symptoms include nausea, vomiting, diarrhea, rhinorrhea, insomnia, agitation, diaphoresis, and myalgias.[14]

Use of the atypical antipsychotics is associated with a metabolic syndrome characterized by type 2 diabetes (increased insulin resistance), dyslipidemia, and hypertension with associated obesity. This is associated with an increased risk for cardiovascular disease.[15, 16]

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Perform laboratory tests depending on the nature of the presentation; patients with simple dystonia may require no tests, and patients with neuroleptic malignant syndrome (NMS) may require multiple tests.

Routine electrolytes, blood urea nitrogen, creatinine, glucose, and bicarbonate are useful in determining hydration status, renal function, acid base status, and in excluding hypoglycemia as the cause for the alteration in sensorium.

Pulse oximetry or arterial blood gas (ABG) sampling is indicated for patients in coma or with depressed gag reflex and diminished respiratory drive.

Because patients with major tranquilizer ingestion are often prescribed other medications, such as tricyclic antidepressants, benzodiazepines, or lithium,[17] appropriate toxicology screening for these substances and for drugs of abuse is indicated. A serum acetaminophen concentration should always be obtained in cases of ingestions with suicidal intent.

Patients with neuroleptic malignant syndrome are critically ill and frequently sustain end-organ damage to the brain, liver, heart, lungs, and kidneys. Consequently, appropriate laboratory tests to monitor such damage are indicated.

The creatine kinase level should be checked. Continuous muscle contraction often produces muscle breakdown that is reflected by an increase in potassium, uric acid, and creatine kinase–MM. Massive elevation of creatine kinase levels into the 100,000 U/L range may occur and portends a significant risk of renal injury. Elevation of total creatine kinase higher than 3 times normal levels occurs in 50-100% of cases.

Urinalysis should be performed. Muscle breakdown products (eg, myoglobin) precipitate in the kidney, and tubular dysfunction may occur. Dehydration promotes this precipitation. Urinalysis may reveal a moderate-to-strong reaction on the dipstick for occult blood. Microscopic analysis typically reveals very few red blood cells, which is indirect evidence for the presence of myoglobinuria. In advanced myoglobinuria, the urine is dark brown. Urine specific gravity and hourly output can guide rehydration efforts. Myoglobin assays can be performed to confirm the diagnosis but usually are not required.

Liver enzyme levels may be altered. Severe sustained hyperthermia can result in hepatic necrosis, which is reflected in significant elevation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and glutamic-pyruvic transaminase (GPT) liver enzymes.

Coagulation profile changes may occur in patients with NMS, who are prone to develop a coagulopathy or disseminated intravascular coagulation (DIC). Establish baseline levels of prothrombin time (PT), activated partial thromboplastin time (aPTT), platelets, and fibrinogen.

Various infections and septic shock may resemble NMS. Obtain a lactate level and blood, urine, and sputum cultures and perform a lumbar puncture to obtain cerebrospinal fluid (CSF) after a head CT for examination and culture.

Consider thyroid function tests (TFTs) because thyrotoxicosis can present with many features similar to NMS.

Qualitative assays for detection of antipsychotics are not widely available. In addition, serum drug levels for major tranquilizers do not correlate well with the clinical severity of the overdose and are not useful in acute treatment.

Imaging Studies

No specific imaging studies are routinely required; however, if appropriate, the patient's individual condition may require imaging.

Chest radiographs are important in patients requiring intubation and in those with any respiratory distress. Comatose patients are at risk for aspiration, and chest radiographs are routinely obtained for this reason.

Kidney-ureter-bladder (KUB) radiographs may be helpful because phenothiazines are radiopaque and are often observed on a plain film of the abdomen. This may be useful if the ingestion is unknown and may help quantify the number of pills taken if the study is performed soon after ingestion. If obtained, KUB radiographs should be performed before administration of activated charcoal because it may hinder radiographic visualization. KUB radiographs cannot be used to rule out phenothiazine exposure.

CT scans of the head without contrast are indicated in some cases. Although not all patients with major tranquilizer ingestion require a CT scan of the head, it may be useful in comatose patients, those with seizures or status epilepticus, and in patients with focal neurologic deficits.

Other Tests

A 12-lead ECG and cardiac monitoring are indicated to look for potentially serious lengthening of the QT interval, AV block, or dysrhythmias. Symptoms generally present within 6 hours of ingestion; thus, monitoring patients for at least 6 hours is recommended.

Ferric chloride or Phenistix test results can be positive with very high concentrations of phenothiazines in the urine; however, owing to a lack of sensitivity and specificity, their use as bedside tests is rarely indicated.

Procedures

A lumbar puncture is indicated, usually following CT scan of the brain, because meningitis may present in a manner similar to NMS (high fever, altered mental status).

 

Treatment

Approach Considerations

No specific antidotes exist for the adverse effects of neuroleptic medications. Because these effects are so diverse and do not occur in most cases, prophylactic treatment for seizures, dystonia, dysrhythmias, or neuroleptic malignant syndrome (NMS) is not indicated.

Patients with an acute overdose of neuroleptic medication can be transferred if they are stable for a period of 6 hours. Transferring a patient before 6 hours of observation is imprudent because of the risk of developing seizures, hypotension, and dysrhythmias. Patients with NMS are critically ill and generally are not candidates for transfer, unless the initial treating facility is unable to provide adequate medical care. Once the patient appears to be improving and is clinically stable with decreasing creatine kinase levels and normal mentation, transfer may be undertaken safely.

Prehospital Care

Be aware that patients with an antipsychotic (neuroleptic) overdose are at risk of rapid deterioration with coma, seizures, hypotension, or dysrhythmias. They all require transport to a hospital facility because the severity of overdose cannot be ascertained immediately after ingestion.

Treatment with activated charcoal, 1 g/kg, is indicated as soon as possible. This can be administered in the field if permitted by local protocol and if altered mental status does not create a risk for aspiration.

Establish a large-bore intravenous (IV) line of isotonic sodium chloride solution in anticipation of possible hypotension or the need to administer medications.

Seizure activity usually responds to benzodiazepines in the usual anticonvulsant doses.

Treat ventricular dysrhythmias with standard advanced cardiac life support (ACLS) pharmaceutical agents.

Emergency Department Care

Emergency department care varies depending on the patient's condition and on the care already provided in the field. The standard approach to resuscitation (airway, breathing, circulation, drugs, and environment [ABCDE]) is used as indicated by the patient's condition. Active airway management is indicated for patients who are in shock, status epilepticus, coma, or cardiac arrest.

No specific antidote for any of the neuroleptics exists.

Gastrointestinal (GI) decontamination (gastric lavage), if used within an hour of ingestion, may be useful in decreasing the absorption of neuroleptics. Protect the patient's airway before lavage if an altered level of consciousness is present. Patients sick enough to require intubation for their clinical condition should also be lavaged. Activated charcoal remains the GI decontamination method of choice. Neuroleptics are generally well bound by activated charcoal and should be administered in standard doses as soon as possible postingestion. Multiple-dose activated charcoal is of limited benefit and cannot be used if an ileus is present. Ipecac syrup is never recommended.

Hemoperfusion, hemodialysis, and forced diuresis are not effective.

Seizures are treated in a stepwise fashion, beginning with benzodiazepines (eg, lorazepam, midazolam) and followed by barbiturates (eg, phenobarbital, pentobarbital).

The combination of peripheral alpha-blockade and dehydration may result in severe hypotension during major tranquilizer overdose. Initial treatment involves administration of a volume challenge with isotonic saline. If the patient remains hypotensive after fluid challenge or manifests signs of cardiogenic shock, vasoconstrictor agents may be required. Norepinephrine is the preferred vasoconstrictor in this circumstance because it has direct alpha-agonist effects. Paradoxically, epinephrine or dopamine may lower the blood pressure because alpha-blockade from major tranquilizer exposure causes unopposed beta-agonist peripheral vasodilation.

Placement of a Foley catheter may be necessary in cases of the following:

  • Coma
  • Shock or severe dehydration (in order to monitor urine output)
  • Urinary retention from the anticholinergic effects of the overdose

For patients manifesting neuroleptic malignant syndrome (NMS) with worsening hyperthermia, immediate cooling measures (eg, fans, wet cloths, ice packs in groin and axilla, and rectal acetaminophen) are indicated. Severe hyperthermia should be treated aggressively and rapidly with ice bath immersion.

Bromocriptine and amantadine are central dopaminergic agonists that may be effective in reversing the dopaminergic blockade caused by the neuroleptics. They have been reported as effective in treating NMS but work slowly (eg, over several days). They are given orally or by nasogastric tube, and they should be tapered gradually to avoid precipitation of another episode of NMS.

Oral levodopa, with or without carbidopa, and intravenous levodopa are therapies used more commonly in patients with Parkinson disease who develop NMS on sudden withdrawal of their dopaminergic therapy. Steroid pulse therapy may be useful in NMS for reducing the illness duration and improving symptoms in patients with Parkinson disease.

Dantrolene sodium (1-10 mg/kg) may be considered as adjunctive therapy for patients manifesting severe hyperthermia (rectal temperatures > 105°F [40.6º C]) and significant muscle rigidity. Dantrolene is incompatible with acidic solutions and is mixed with sterile water for injection. It must be given directly by slow IV push or by IV piggyback into a large-bore IV near the catheter with the IV fluid shut off. Great care must be taken to avoid extravasation into the tissues. Dantrolene is given in 1-2 mg/kg doses until a maximum dose of 10 mg/kg or until the rectal temperature breaks.

Dantrolene may be effective in malignant hyperthermia by dissociating the excitation-contraction coupling of skeletal muscles. While the precise mechanism of action and molecular targets are still incompletely known, dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. In 2004, Krause et al stated that studies have identified the ryanodine receptor (the major calcium release channel of the skeletal muscle sarcoplasmic reticulum) as a dantrolene-binding site.[18] A direct or indirect inhibition of the ryanodine receptor is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration.

Dantrolene acts primarily peripherally and has no effect on the cardiovascular or respiratory systems in this acute setting.

Some studies have questioned the efficacy of dantrolene,[19] but anecdotal reports still advocate for its use. Dantrolene should not be used as monotherapy.

Patients who develop signs of potentially serious toxicity require admission. Patients who remain asymptomatic after a period of observation (6 h recommended) can be discharged home or given psychiatric evaluation.[20]

Potentially serious signs of toxicity include persistent hypotension, dysrhythmias or abnormal ECG, seizures, or movement disorders that fail to respond to anticholinergic treatment.

Patients with dysrhythmias, status epilepticus, coma, or those who require pressor agents to maintain blood pressure should be treated in an ICU setting.

Repeated doses of activated charcoal every 6 hours without cathartics may increase clearance of some neuroleptics that undergo enterohepatic circulation. There must be no ileus of the gut for this method of enhanced elimination. Perform standard measures for treating comatose patients (eg, eye care, position changes).

Follow-up with a psychiatrist is recommended for patients with intentional overdose and for those who require medication changes because of adverse effects from neuroleptics. Once the patient is stable and awake, psychiatric evaluation can take place before discharge from hospital.

Consultations

Notification of the regional poison control center is indicated. In complex or severe cases, consult with the regional poison control center or a medical toxicologist for additional information and patient care recommendations. Once the patient's medical condition has stabilized, psychiatric assessment may be indicated to determine any suicidal intent.

Prevention

Medications should be labeled and stored safety. Child-resistant closures should be applied to all medications and substances that can cause significant toxicity. 

Long-Term Monitoring

Most patients with neuroleptic overdose recover without sequelae and do not require ongoing medical treatment.

Patients who have developed neuroleptic malignant syndrome (NMS) pose a difficult problem if they require ongoing antipsychotic medication monitoring and adjustment. Neuroleptics have been successfully reintroduced following episodes of NMS, but this must be done carefully and under the supervision of a psychiatrist. Alternative medications with a lower potency that are less likely to produce NMS may be used.

 

Medication

Medication Summary

No specific antidotes exist for neuroleptic drug toxicity. Gastrointestinal decontaminants may be used to minimize systemic absorption. Symptom-directed therapy may be used to counter neuroleptic effects on specific organ systems.

GI decontaminants

Class Summary

Empirically used to minimize systemic absorption of the toxin. May only be of benefit if administered within 1-2 h of ingestion.

Activated charcoal (Liqui-Char)

Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

For maximum effect, administer within 30 min of ingesting poison.

Generally mixed and administered with a saline cathartic (do not use sorbitol).

Anticonvulsants

Class Summary

Indicated for seizures and status epilepticus associated with major tranquilizer overdose. Compared to lorazepam, advantages of diazepam are more rapid onset of action and decreased cost. The disadvantage is that diazepam has a brief duration of anticonvulsant activity (20 min) compared to lorazepam (several hours). Both drugs can aggravate hypotension, which may limit their usefulness in this setting.

Barbiturates are usually not necessary in neuroleptic overdose because most patients respond to benzodiazepines. Phenobarbital is the most commonly used anticonvulsant, but shorter-acting barbiturates are also effective.

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Seizures are relatively common in association with major tranquilizer overdose because most neuroleptics lower seizure threshold. In the ED, standard protocol is used for terminating seizures.

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life.

By increasing the action of GABA, a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.

Monitoring blood pressure after administering dose is important. Adjust prn.

Midazolam (Versed)

Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access

Phenobarbital (Barbita, Luminal)

Interferes with transmission of impulses from thalamus to cortex of brain. Effective in terminating convulsions, but use is often limited by hypotension associated with neuroleptic overdose.

Cardiovascular agents

Class Summary

Use of direct-acting alpha-agonists is preferred when hypotension persists after adequate volume challenge with isotonic sodium chloride solution IV. Pressors with actions at beta- and alpha-receptors (eg, dopamine, epinephrine) may exert only a beta (vasodilatory) effect in the face of neuroleptic-induced alpha blockade; consequently, a paradoxical drop in blood pressure may occur if the pressors are used.

Dysrhythmias are relatively common in neuroleptic overdose. Prolongation of the QT interval may result in torsade de pointes. The quinidinelike effect on the slope of phase 0 of the ECG may result in widening of the QRS. Magnesium may be an effective treatment.

Norepinephrine (Levophed)

Stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases.

Magnesium sulfate

Currently DOC for treatment of torsade de pointes and may be an effective antiarrhythmic for ventricular and supraventricular tachycardia.

Skeletal muscle relaxant

Class Summary

Dantrolene is currently recommended as treatment for hyperthermia associated with neuroleptic malignant syndrome. Acts to restore calcium entry into muscle sarcoplasmic reticulum, causing muscle relaxation and decreasing heat production from muscle.

Dantrolene (Dantrium)

Stimulates muscle relaxation by modulating skeletal muscle contractions at site beyond myoneural junction and acting directly on muscle itself.

Antihistamines

Class Summary

Agents with anticholinergic properties are effective in terminating acute dystonias associated with neuroleptic use.

Diphenhydramine (Benadryl)

Anticholinergic medications help restore balance between dopaminergic and cholinergic neurotransmission. Dopaminergic transmission is decreased by neuroleptic drugs.

Dopamine agonist

Class Summary

Can reverse the dopamine blockade caused by neuroleptics and has been reported to be useful in reversing NMS symptoms.

Bromocriptine (Parlodel)

Semisynthetic ergot alkaloid derivative. Strong D2-receptor agonist, partial D1-receptor agonist. Stimulates dopamine receptors in corpus striatum.

Approximately 28% absorbed from the GI tract and metabolized in the liver. Approximate elimination half-life is 50 h with 85% excreted in feces and 3-6% eliminated in urine.

Amantadine (Symmetrel)

Inhibits N-methyl-D-aspartic acid (NMDA) receptor-mediated stimulation of acetylcholine release in rat striatum. May enhance dopamine release, inhibit dopamine reuptake, stimulate postsynaptic dopamine receptors, or enhance dopamine receptor sensitivity.