Second generation (atypical) antipsychotic medication poisoning
- Raffi Kapitanyan, MD
Raffi Kapitanyan, MD
- Assistant Professor, Department of Emergency Medicine
- Robert Wood Johnson Medical School
- Mark Su, MD, MPH
Mark Su, MD, MPH
- Clinical Associate Professor of Emergency Medicine
- New York University School of Medicine
- Section Editors
- Stephen J Traub, MD
Stephen J Traub, MD
- Section Editor — Toxicology
- Associate Professor of Emergency Medicine
- Mayo Medical School
- Michele M Burns, MD, MPH
Michele M Burns, MD, MPH
- Section Editor — Pediatric Toxicology
- Assistant Professor of Pediatrics and Emergency Medicine
- Harvard Medical School
- Deputy Editor
- Jonathan Grayzel, MD, FAAEM
Jonathan Grayzel, MD, FAAEM
- Senior Deputy Editor — UpToDate
- Deputy Editor — Adult and Pediatric Emergency Medicine
- Deputy Editor — Primary Care Sports Medicine (Adolescents and Adults)
- Assistant Professor of Emergency Medicine
- University of Massachusetts Medical School
A second generation of antipsychotic medications, commonly referred to as "atypical antipsychotics," was introduced in 1998. The term "atypical" refers to an antipsychotic medication that produces minimal extrapyramidal side effects (EPS) at clinically effective antipsychotic doses, has a low propensity to cause tardive dyskinesia (TD) with long-term treatment, and treats both positive and negative signs and symptoms of schizophrenia . Atypical agents currently available include clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), and paliperidone (Invega), the active metabolite of risperidone.
Atypical antipsychotics have largely replaced traditional agents as first-line therapy in the treatment of schizophrenia. Toxicologic exposures and fatalities associated with atypical agents pose a persistent problem in the United States and elsewhere [2-4]. Consequently, it is important for the practicing clinician to be familiar with the pharmacology and toxicology of these medications.
This topic review will discuss the basic pharmacology, presentation, and management of acute intoxication with atypical antipsychotics. Discussions of the clinical use of these drugs, details concerning potential side effects, and general management of drug overdose are found elsewhere. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects" and "Neuroleptic malignant syndrome" and "General approach to drug poisoning in adults".)
PHARMACOLOGY AND CELLULAR TOXICOLOGY
The pharmacology of atypical antipsychotic agents is complex. As a general rule, all exhibit dopamine (D2) receptor blockade, similar to first-generation antipsychotics, but with a lower binding affinity . In addition to lower D2 receptor potency and occupancy at therapeutic doses, atypical agents selectively antagonize mesolimbic D2 receptors more so than those in the nigrostriatum and prefrontal cortex. As a result, side effects attributable to nigrostriatal D2 blockade (eg, extrapyramidal symptoms, such as acute dystonia, parkinsonism, akathisia, and tardive dyskinesia) occur less frequently, as do side effects attributable to mesocortical (ie, prefrontal) D2 blockade (eg, neurocognitive impairment and negative symptoms).
Atypical antipsychotics are also serotonin (5-HT) antagonists at the 5-HT2A receptor subtype. This pharmacologic effect mitigates the negative signs and symptoms of schizophrenia by disinhibiting the dopamine system in the nigrostriatum and prefrontal cortex .
- Freedman R. Schizophrenia. N Engl J Med 2003; 349:1738.
- Bronstein AC, Spyker DA, Cantilena LR Jr, et al. 2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th Annual Report. Clin Toxicol (Phila) 2009; 47:911.
- Gill JS, Pillai SK, Koh OH, Jambunathan S. [Non-fatal paliperidone overdose: a case report]. Turk Psikiyatri Derg 2010; 21:331.
- Mowry JB, Spyker DA, Cantilena LR Jr, et al. 2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol (Phila) 2013; 51:949.
- Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. J Toxicol Clin Toxicol 2001; 39:1.
- Richelson E. Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry 1999; 60 Suppl 10:5.
- B, Thakurta S. Drug Class Review: Atypical Antipsychotic Drugs: Final Report Update 2. Portland, (OR): Oregon Health & Science University; 2008 Jun. www.ohsu.edu/drugeffectiveness/reports/final.cfm.
- Lofton AL, Klein-Schwartz W. Atypical experience: a case series of pediatric aripiprazole exposures. Clin Toxicol (Phila) 2005; 43:151.
- Seifert SA, Schwartz MD, Thomas JD. Aripiprazole (abilify) overdose in a child. Clin Toxicol (Phila) 2005; 43:193.
- Tamminga CA. Similarities and differences among antipsychotics. J Clin Psychiatry 2003; 64 Suppl 17:7.
- Fang J, Gorrod JW. Metabolism, pharmacogenetics, and metabolic drug-drug interactions of antipsychotic drugs. Cell Mol Neurobiol 1999; 19:491.
- Meli M, Rauber-Lüthy C, Hoffmann-Walbeck P, et al. Atypical antipsychotic poisoning in young children: a multicentre analysis of poisons centres data. Eur J Pediatr 2014; 173:743.
- Ngo A, Ciranni M, Olson KR. Acute quetiapine overdose in adults: a 5-year retrospective case series. Ann Emerg Med 2008; 52:541.
- Trenton A, Currier G, Zwemer F. Fatalities associated with therapeutic use and overdose of atypical antipsychotics. CNS Drugs 2003; 17:307.
- Rauber-Lüthy C, Hofer KE, Bodmer M, et al. Gastric pharmacobezoars in quetiapine extended-release overdose: a case series. Clin Toxicol (Phila) 2013; 51:937.
- Caravati EM, Juenke JM, Crouch BI, Anderson KT. Quetiapine cross-reactivity with plasma tricyclic antidepressant immunoassays. Ann Pharmacother 2005; 39:1446.
- Duggan L, Fenton M, Rathbone J, et al. Olanzapine for schizophrenia. Cochrane Database Syst Rev 2005; :CD001359.
- Srisurapanont M, Maneeton B, Maneeton N. Quetiapine for schizophrenia. Cochrane Database Syst Rev 2004; :CD000967.
- Gilbody SM, Bagnall AM, Duggan L, Tuunainen A. Risperidone versus other atypical antipsychotic medication for schizophrenia. Cochrane Database Syst Rev 2000; :CD002306.
- Jayaram MB, Hosalli P. Risperidone versus olanzapine for schizophrenia. Cochrane Database Syst Rev 2005; :CD005237.
- Bagnall A, Lewis RA, Leitner ML. Ziprasidone for schizophrenia and severe mental illness. Cochrane Database Syst Rev 2000; :CD001945.
- El-Sayeh HG, Morganti C. Aripiprazole for schizophrenia. Cochrane Database Syst Rev 2004; :CD004578.
- Pollak PT, Zbuk K. Quetiapine fumarate overdose: clinical and pharmacokinetic lessons from extreme conditions. Clin Pharmacol Ther 2000; 68:92.
- Palenzona S, Meier PJ, Kupferschmidt H, Rauber-Luethy C. The clinical picture of olanzapine poisoning with special reference to fluctuating mental status. J Toxicol Clin Toxicol 2004; 42:27.
- Balicka-Slusarczyk B, Szczeklik J, Szpak D, Groszek B. [Clinical course of acute poisoning with olanzapine]. Przegl Lek 2005; 62:489.
- Hodge CH, Jewell M, Gummin DD, Leikin JB. Atypical presentation of risperidone toxicity. Vet Hum Toxicol 2001; 43:339.
- Magdalan J, Wasyko-Smolarek M, Antończyk A, et al. [Intoxications with atypical antipsychotic drugs--data of the Acute Intoxication Unit in Wrocław]. Przegl Lek 2004; 61:392.
- Chue P, Singer P. A review of olanzapine-associated toxicity and fatality in overdose. J Psychiatry Neurosci 2003; 28:253.
- Burton S, Heslop K, Harrison K, Barnes M. Ziprasidone overdose. Am J Psychiatry 2000; 157:835.
- House M. Overdose of ziprasidone. Am J Psychiatry 2002; 159:1061.
- Biswas AK, Zabrocki LA, Mayes KL, Morris-Kukoski CL. Cardiotoxicity associated with intentional ziprasidone and bupropion overdose. J Toxicol Clin Toxicol 2003; 41:101.
- Liberty IF, Todder D, Umansky R, Harman-Boehm I. Atypical antipsychotics and diabetes mellitus: an association. Isr Med Assoc J 2004; 6:276.
- Leslie DL, Rosenheck RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry 2004; 161:1709.
- Stergiou V, Bozikas VP, Garyfallos G, et al. Olanzapine-induced leucopenia and neutropenia. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:992.
- Dubois D. Toxicology and overdose of atypical antipsychotic medications in children: does newer necessarily mean safer? Curr Opin Pediatr 2005; 17:227.
- Antia SX, Sholevar EH, Baron DA. Overdoses and ingestions of second-generation antipsychotics in children and adolescents. J Child Adolesc Psychopharmacol 2005; 15:970.
- Capel MM, Colbridge MG, Henry JA. Overdose profiles of new antipsychotic agents. Int J Neuropsychopharmacol 2000; 3:51.
- Chyka PA, Seger D. Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997; 35:721.
- Ananth J, Parameswaran S, Gunatilake S, et al. Neuroleptic malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry 2004; 65:464.
- Hanft A, Eggleston CF, Bourgeois JA. Neuroleptic malignant syndrome in an adolescent after brief exposure to olanzapine. J Child Adolesc Psychopharmacol 2004; 14:481.
- LeBlaye, I, Donatini, B, Hall, M, Krupp, P. Acute overdosage with clozapine: A review of the available clinical experience. Pharmaceutical Med 1992; 6:169.
- Ferraro, KK, Burkhart, KK, Donovan, JW, O'Donnell, SJ. A retrospective review of physostigmine in olanzapine overdose. J Toxicol Clin Toxicol 2001; 39:474.
- Weizberg M, Su M, Mazzola JL, et al. Altered mental status from olanzapine overdose treated with physostigmine. Clin Toxicol (Phila) 2006; 44:319.
- Burns MJ, Linden CH, Graudins A, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med 2000; 35:374.
- Bartos M, Knudsen K. Use of intravenous lipid emulsion in the resuscitation of a patient with cardiovascular collapse after a severe overdose of quetiapine. Clin Toxicol (Phila) 2013; 51:501.
- Yurtlu BS, Hanci V, Gür A, Turan IO. Intravenous lipid infusion restores consciousness associated with olanzapine overdose. Anesth Analg 2012; 114:914.
- Cheng-Shannon J, McGough JJ, Pataki C, McCracken JT. Second-generation antipsychotic medications in children and adolescents. J Child Adolesc Psychopharmacol 2004; 14:372.
- Catalano G, Catalano MC, Nunez CY, Walker SC. Atypical antipsychotic overdose in the pediatric population. J Child Adolesc Psychopharmacol 2001; 11:425.
- Catalano G, Cooper DS, Catalano MC, Butera AS. Olanzapine overdose in an 18-month-old child. J Child Adolesc Psychopharmacol 1999; 9:267.
- Theisen FM, Grabarkiewicz J, Fegbeutel C, et al. Olanzapine overdose in children and adolescents: two case reports and a review of the literature. J Child Adolesc Psychopharmacol 2005; 15:986.
- PHARMACOLOGY AND CELLULAR TOXICOLOGY
- CLINICAL FEATURES OF OVERDOSE
- History and physical examination
- - Possible historical features
- - Possible examination findings
- LABORATORY EVALUATION
- DIFFERENTIAL DIAGNOSIS
- General management
- Decontamination and enhanced elimination
- Extrapyramidal and anticholinergic effects
- Refractory toxicity
- PEDIATRIC CONSIDERATIONS
- ADDITIONAL RESOURCES
- SUMMARY AND RECOMMENDATIONS