Neuroleptic Agent Toxicity

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

 

Next:

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.

Previous
Next:

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]

Previous
Next:

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. 

Previous
Next:

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]  

Previous
Next:

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.

Previous