Neuroleptic Agent Toxicity 

  • Author: Kathryn Ruth Challoner, MD, MPH, FACEP; Chief Editor: Asim Tarabar, MD   more...
 
Updated: Jun 23, 2010
 

Background

The neuroleptic agents (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:

  • Butyrophenones (eg, droperidol, haloperidol)
  • Dibenzoxazepines (eg, loxapine) - Loxapine (Loxitane) at lower doses exerts an atypical profile (≤ 50 mg/d).
  • Dihydroindolone (eg, molindone) - Molindone (Moban) tablets have been discontinued.
  • Diphenylbutylpiperidine (eg, pimozide, which is used to treat Tourette syndrome)
  • Phenothiazines, further divided into the aliphatics, piperidines, and piperazines
  • Thioxanthenes (eg, thiothixene)

Neuroleptics also are used as sedatives and 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 side effects, the newer (second-generation) antipsychotic agents were introduced beginning in the 1970s. The newer atypical antipsychotic agents include the following:

  • Benzepines
    • Clozapine (Clozaril) - A dibenzodiazepine: high affinity for D4 receptor; use limited by its side effects
    • Olanzapine (Zyprexa) - A thienobenzodiazepine
    • Quetiapine (Seroquel) - A dibenzothiazepine
  • Indoles
    • Ziprasidone (Geodon)
  • Quinolinones
    • Aripiprazole (Abilify): Partial agonism at the D-2 receptor
  • (9-hydroxyrisperidone) paliperidone (Invega)
  • Melperone - A butyrophenone in clinical trial in the United States
  • Zotepine[1] (Nipolept)
  • Benzisoxazole: Risperidone (Risperdal) - An indole

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

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 owing to antagonism of central dopaminergic (D-2 receptor) neurotransmission, although they also have antagonist effects at muscarinic, serotonergic, alpha1-adrenergic, and H1-histaminergic receptors.

The newer atypical antipsychotics also have D-2 receptor antagonism, and most have 5-HT2 receptor antagonism. Aripiprazole does not have serotonin activity but has some partial dopamine agonism. These drugs have less chance of causing extrapyramidal side effects and a sustained elevated prolactin levels but have further serious metabolic side effects associated with their use.

Although all antipsychotic preparations share some toxic characteristics, the relative intensity of these effects varies greatly, depending on the individual drug. 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[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. Chronic use of major tranquilizers is associated with buccolingual movements (tardive dyskinesia [TD]), parkinsonism, and akathisia.
  • Neuroleptic malignant syndrome[2]
    • All of the major tranquilizers have been implicated in the development of neuroleptic malignant syndrome (NMS), a life-threatening derangement that affects multiple organ systems and results in significant mortality.
    • Hypothalamic D-2 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 D-2 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 can result in arrhythmias.
  • 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 overdose.
  • Hypothermia: Certain major tranquilizers can prevent shivering, limiting the body's ability to generate heat.
Previous
Next

Epidemiology

Frequency

United States

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 on the street by drug users, who may then develop adverse effects (eg, dystonia). Increased overdose is now being seen in elderly persons, although some toxicity may be 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 FDA for use in the United States.

Mortality/Morbidity

Mortality is relatively rare with overdose of antipsychotic medication. However, if neuroleptic malignant syndrome occurs, the mortality rate can reach up to 10-12%.

  • It is not uncommon for patients to be taking 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.

Race

No scientific data have noted a difference in outcome of neuroleptic overdose that is attributable to race.

Sex

Certain adverse effects of neuroleptic overdose are most common in males, while others are most common in females. For example, TD 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. This may be related to changes in metabolism or interaction with the use of multiple other drugs.

Previous
Proceed to Clinical Presentation
 
 
Contributor Information and Disclosures
Author

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.

Coauthor(s)

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.

Specialty Editor Board

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, and Society of Critical Care 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  Director of Medical Toxicology, Allegheny General Hospital

Disclosure: Nothing to disclose.

John D Halamka, MD, MS  Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

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.

References

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

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

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

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

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

  6. 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].

  7. Ananth J, Parameswaran S, Gunatilake S. Side effects of atypical antipsychotic drugs. Curr Pharm Des. 2004;10(18):2219-29. [Medline].

  8. Ananth J, Parameswaran S, Gunatilake S, et al. Neuroleptic malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry. Apr 2004;65(4):464-70. [Medline].

  9. Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin. May 2004;22(2):389-411. [Medline].

  10. Brady WA. Life threatening syndromes presenting with altered mentation and muscular rigidity. Emerg Med Rep. 1999;20:5160.

  11. Capel MM, Colbridge MG, Henry JA. Overdose profiles of new antipsychotic agents. Int J Neuropsychopharmacol. Mar 2000;3(1):51-54. [Medline].

  12. Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am. May 2000;18(2):317-25, x. [Medline].

  13. 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. Jan 2006;15(1):177-206. [Medline].

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

  15. Ener RA, Meglathery SB, Van Decker WA, Gallagher RM. Serotonin syndrome and other serotonergic disorders. Pain Med. Mar 2003;4(1):63-74. [Medline].

  16. Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-32. [Medline].

  17. Fleishman SB, Lavin MR, Sattler M, Szarka H. Antiemetic-induced akathisia in cancer patients receiving chemotherapy. Am J Psychiatry. May 1994;151(5):763-5. [Medline].

  18. 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].

  19. Gil-ad I, Shtaif B, Shiloh R, Weizman A. Evaluation of the neurotoxic activity of typical and atypical neuroleptics: relevance to iatrogenic extrapyramidal symptoms. Cell Mol Neurobiol. Dec 2001;21(6):705-16. [Medline].

  20. Hasan S, Buckley P. Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique. Am J Psychiatry. Aug 1998;155(8):1113-6. [Medline].

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

  22. Heiman-Patterson TD. Neuroleptic malignant syndrome and malignant hyperthermia. Important issues for the medical consultant. Med Clin North Am. Mar 1993;77(2):477-92. [Medline].

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

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

  25. Knight ME, Roberts RJ. Phenothiazine and butyrophenone intoxication in children. Pediatr Clin North Am. Apr 1986;33(2):299-309. [Medline].

  26. Le Blaye I, Donatini B, Hall M. Acute overdosage with clozapine: A review of the available clinical experience. Pharm Med. 1992;6:169.

  27. Le Blaye I, Donatini B, Hall M, Krupp P. Acute overdosage with thioridazine: a review of the available clinical exposure. Vet Hum Toxicol. Apr 1993;35(2):147-50. [Medline].

  28. Lee SH, Yang YY. Reversible neurotoxicity induced by a combination of clozapine and lithium: a case report. Zhonghua Yi Xue Za Zhi (Taipei). Mar 1999;62(3):184-7. [Medline].

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

  30. McCarron MM, Boettger ML, Peck JJ. A case of neuroleptic malignant syndrome successfully treated with amantadine. J Clin Psychiatry. Sep 1982;43(9):381-2. [Medline].

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

  32. Nicholson D, Chiu W. Neuroleptic malignant syndrome. Geriatrics. Aug 2004;59(8):36, 38-40. [Medline].

  33. Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?. Curr Pharm Des. 2004;10(20):2463-75. [Medline].

  34. Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv. Sep 1998;49(9):1163-72. [Medline].

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

  36. Sachdev P, Mason C, Hadzi-Pavlovic D. Case-control study of neuroleptic malignant syndrome. Am J Psychiatry. Aug 1997;154(8):1156-8. [Medline].

  37. Sakkas P, Davis JM, Janicak PG, Wang ZY. Drug treatment of the neuroleptic malignant syndrome. Psychopharmacol Bull. 1991;27(3):381-4. [Medline].

  38. Sato Y, Asoh T, Metoki N, Satoh K. Efficacy of methylprednisolone pulse therapy on neuroleptic malignant syndrome in Parkinson's disease. J Neurol Neurosurg Psychiatry. May 2003;74(5):574-6. [Medline].

  39. Schneider SM. Neuroleptic malignant syndrome: controversies in treatment. Am J Emerg Med. Jul 1991;9(4):360-2. [Medline].

  40. Titier K, Canal M, Deridet E, et al. Determination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and sudden death in clinical practice. Toxicol Appl Pharmacol. Aug 15 2004;199(1):52-60. [Medline].

  41. Trenton A, Currier G, Zwemer F. Fatalities associated with therapeutic use and overdose of atypical antipsychotics. CNS Drugs. 2003;17(5):307-24. [Medline].

  42. Viejo LF, Morales V, Punal P, et al. Risk factors in neuroleptic malignant syndrome. A case-control study. Acta Psychiatr Scand. Jan 2003;107(1):45-9. [Medline].

  43. Wilt JL, Minnema AM, Johnson RF, Rosenblum AM. Torsade de pointes associated with the use of intravenous haloperidol. Ann Intern Med. Sep 1 1993;119(5):391-4. [Medline].

  44. Zetin M. Psychopharmacohazardology: major hazards of the new generation of psychotherapeutic drugs. Int J Clin Pract. Jan 2004;58(1):58-68. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.