Neuroleptic Agent Toxicity

Updated: Dec 29, 2015
  • Author: Jay T Melton, MD; Chief Editor: Asim Tarabar, MD  more...
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Overview

Background

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, as follows:

Butyrophenones:

  • Droperidol (Dridol)
  • Haloperidol (Haldol)

Dibenzoxazepines:

  • Loxapine (Loxitane) at lower doses exerts an atypical profile (≤50 mg/d)

Diphenylbutylpiperidine:

  • Pimozide, used to treat Tourette syndrome

Phenothiazines; further divided into the following:

  • Aliphatics - Chlorpromazine (Thorazine), promazine (Sparine), levomepromazine, and methotrimeprazine (Levoprome, Nozinan)
  • Piperidines - Mesoridazine (Serentil), thioridazine (Mellaril)
  • Piperazines - Fluphenazine (Prolixin), perphenazine (Trilafon), prochlorperazine (Compazine), trifluoperazine (Stelazine)

Thioxanthenes:

  • Thiothixene (Navane)

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 atypical antipsychotic agents include the following:

Benzopines:

  • Clozapine (Clozaril ) - A dibenzodiazepine; high affinity for D4 receptor; use limited by its adverse effects
  • Olanzapine (Zyprexa) - A thienobenzodiazepine
  • Quetiapine (Seroquel) - A dibenzodiazepine

Indoles:

  • Ziprasidone (Geodon)

Quinolinones:

  • Aripiprazole (Abilify) - Partial agonism at the D2 receptor
  • Paliperidone (Invega) (9-hydroxyrisperidone)
  • Melperone - A butyrophenone widely used in Europe; currently in clinical trials in the United States
  • Zotepine [1] (Nipolept)
  • Benzisoxazole: Risperidone (Risperdal) - An indole

Increasingly, atypical antipsychotics are being used for a growing range of indications such as major depression, anxiety, and insomnia. 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 the first-line treatment agents for these newer indications.

The toxicity of other neuroleptic agents are discussed in other Medscape Reference articles (see Selective Serotonin Reuptake Inhibitor Toxicity and Lithium Toxicity).

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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. Receptor Affinity (Antagonism) Based on Atypical Drugs [2] (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.

Generally, all neuroleptic medications are capable of causing the following symptoms:

  • Anticholinergic effects: Neuroleptic agent toxicity can result in tachycardia; hyperthermia; urinary retention; ileus; mydriasis; toxic psychosis; dry mucous membranes; and hot, dry, flushed skin.
  • Extrapyramidal symptoms [3] : 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) [3] : 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
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Epidemiology

Frequency

United States

Antipsychotics rank in the top 5 substance classes involved in human exposures. [4] 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). Overdose is now occurring more commonly in elderly persons, with some toxicity possibly explained by age-related changes in metabolism.

International

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.

Mortality/Morbidity

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.

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.

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

Toxicity of antipsychotic medications may be increased by co-ingestion of other agents, particularly drugs with similar metabolic pathways. [5]

Long-term use of antipsychotic medications can lead to the development of extrapyramidal symptoms such as parkinsonism, hemiballismus, tardive dyskinesia, and prolonged QT interval. [6]

Metabolic syndrome, most commonly related to long-term olanzapine and clozapine use, is associated with weight gain, diabetes, and cardiovascular disease.

Race

No scientific data suggest any race-based difference in outcome of neuroleptic overdose or adverse drug effects.

Sex

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.

Age

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.

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