Neuroleptic Agent Toxicity

Neuroleptic Agent Toxicity

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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).

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

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 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.

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.

DeSilva P, Fenton M, Rathbone J. Zotepine for schizophrenia. Cochrane Database Syst Rev. 2006 Oct 18. CD001948. [Medline].

Levine M, Ruha AM. Overdose of atypical antipsychotics: clinical presentation, mechanisms of toxicity and management. CNS Drugs. 2012 Jul 1. 26(7):601-11. [Medline].

Haddad PM, Dursun SM. Neurological complications of psychiatric drugs: clinical features and management. Hum Psychopharmacol. 2008 Jan. 23 Suppl 1:15-26. [Medline].

Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015 Dec. 53 (10):962-1147. [Medline].

Laugharne J, Waterreus AJ, Castle DJ, Dragovic M. Screening for the metabolic syndrome in Australia: a national survey of psychiatrists’ attitudes and reported practice in patients prescribed antipsychotic drugs. Australas Psychiatry. 2015 Dec 3. [Medline].

Berling I, Isbister GK. Prolonged QT Risk Assessment in Antipsychotic Overdose Using the QT Nomogram. Ann Emerg Med. 2015 Aug. 66 (2):154-64. [Medline].

Huybrechts KF, Gerhard T, Crystal S, Olfson M, Avorn J, Levin R, et al. Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study. BMJ. 2012 Feb 23. 344:e977. [Medline]. [Full Text].

Drotts DL, Vinson DR. Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med. 1999 Oct. 34(4 Pt 1):469-75. [Medline].

Dilsaver SC, Alessi NE. Antipsychotic withdrawal symptoms: phenomenology and pathophysiology. Acta Psychiatr Scand. 1988 Mar. 77(3):241-6. [Medline].

DE Hert M, Schreurs V, Vancampfort D, VAN Winkel R. Metabolic syndrome in people with schizophrenia: a review. World Psychiatry. 2009 Feb. 8(1):15-22. [Medline]. [Full Text].

Shirzadi AA, Ghaemi SN. Side effects of atypical antipsychotics: extrapyramidal symptoms and the metabolic syndrome. Harv Rev Psychiatry. 2006 May-Jun. 14(3):152-64. [Medline].

McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012 Feb 25. 379(9817):721-8. [Medline].

Krause T, Gerbershagen MU, Fiege M, et al. Dantrolene–a review of its pharmacology, therapeutic use and new developments. Anaesthesia. 2004 Apr. 59(4):364-73. [Medline].

Reulbach U, Dutsch C, Biermann T, Sperling W, Thuerauf N, Kornhuber J, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007. 11(1):R4. [Medline].

Correll CU, Penzner JB, Parikh UH, Mughal T, Javed T, Carbon M. Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child Adolesc Psychiatr Clin N Am. 2006 Jan. 15(1):177-206. [Medline].

Dubois D. Toxicology and overdose of atypical antipsychotic medications in children: does newer necessarily mean safer?. Curr Opin Pediatr. 2005 Apr. 17(2):227-33. [Medline].

Gareri P, De Fazio P, De Fazio S, Marigliano N, Ferreri Ibbadu G, De Sarro G. Adverse effects of atypical antipsychotics in the elderly: a review. Drugs Aging. 2006. 23(12):937-56. [Medline].

Haupt DW. Differential metabolic effects of antipsychotic treatments. Eur Neuropsychopharmacol. 2006 Sep. 16 Suppl 3:S149-55. [Medline].

Herrmann N, Lanctot KL. Do atypical antipsychotics cause stroke?. CNS Drugs. 2005. 19(2):91-103. [Medline].

Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: a systematic review. Drug Saf. 2005. 28(11):1029-44. [Medline].

Love JN, Smith JA, Simmons R. Are one or two dangerous? Phenothiazine exposure in toddlers. J Emerg Med. 2006 Jul. 31(1):53-9. [Medline].

Minns AB, Clark RF. Toxicology and overdose of atypical antipsychotics. J Emerg Med. 2012 Nov. 43(5):906-13. [Medline].

Newcomer JW, Haupt DW. The metabolic effects of antipsychotic medications. Can J Psychiatry. 2006 Jul. 51(8):480-91. [Medline].

Pierre JM. Extrapyramidal symptoms with atypical antipsychotics : incidence, prevention and management. Drug Saf. 2005. 28(3):191-208. [Medline].

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.

Jay T Melton, MD Resident Physician, Department of Emergency Medicine, Kings County Hospital, State University of New York Downstate Medical Center

Disclosure: Nothing to disclose.

Sage W Wiener, MD Assistant Professor, Department of Emergency Medicine, State University of New York Downstate Medical Center; Director of Medical Toxicology, Department of Emergency Medicine, Kings County Hospital Center

Sage W Wiener, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph’s Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Fred Harchelroad, MD, FACMT, FAAEM, FACEP Attending Physician in Emergency Medicine and Medical Toxicology, Excela Health System

Fred Harchelroad, MD, FACMT, FAAEM, FACEP is a member of the following medical societies: American College of Medical Toxicology

Disclosure: Nothing to disclose.

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Peter MC DeBlieux, MD Professor of Clinical Medicine and Pediatrics, Section of Pulmonary and Critical Care Medicine, Program Director, Department of Emergency Medicine, Louisiana State University School of Medicine in New Orleans

Peter MC DeBlieux, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Radiological Society of North America, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Kathryn Ruth Challoner, MD, MPH, FACEP Clinical Professor of Emergency Medicine, Department of Emergency Medicine, Keck School of Medicine of the University of Southern California

Kathryn Ruth Challoner, MD, MPH, FACEP is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

Edward J Newton, MD, FACEP, FRCPC Professor of Clinical Emergency Medicine, Chairman, Department of Emergency Medicine, University of Southern California Keck School of Medicine

Edward J Newton, MD, FACEP, FRCPC is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Royal College of Physicians and Surgeons of Canada, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Neuroleptic Agent Toxicity

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