Abstract
Since 1989, several novel antipsychotic drugs have become available for use including clozapine, risperidone, olanzapine, quetiapine and ziprasidone. These agents represent a substantial improvement in the treatment of schizophrenia and related disorders and are considered to have a favourable adverse effect profile relative to traditional antipsychotics. Nonetheless, in rare cases, people have died as a result of taking atypical antipsychotic drugs at therapeutic and supratherapeutic doses. Toxic doses of atypical antipsychotics are highly variable: some patients have died while taking therapeutic doses and others have survived massive overdoses. Toxicity may be increased by coingestion of other agents, particularly drugs with similar metabolic pathways. Atypical antipsychotics are metabolised predominantly by cytochrome P450 (CYP) isoenzymes, particularly CYP1A2 (clozapine and olanzapine), CYP3A4 (clozapine, quetiapine and ziprasidone) and CYP2D6 (olanzapine and risperidone). Concurrent prescription of other drugs that inhibit these isoenzymes may increase the probability of adverse events in patients taking atypical antipsychotics. Deaths due to atypical antipsychotic toxicity are often related to cardiovascular complications, but pulmonary, neurological, endocrine and gastrointestinal complications have also caused fatalities. Prevention and management of atypical antipsychotic overdose are of increased clinical relevance as prescription of these drugs increases
Similar content being viewed by others
References
Bums MJ. The pharmacology and toxicology of atypical anti-psychotic agents. Clin Toxicol 2001; 39: 1–14
Henderson DC. Clinical experience with insulin resistance, diabetic ketoacidosis, and type 2 diabetes mellitus in patients treated with atypical antipsychotic agents. J Clin Psychiatry 2001; 62 Suppl. 27: 10–4
Von Hayek D, Huttl V, Reiss J, et al. Hyperglycemia and ketoacidosis associated with olanzapine. Nervenarzt 1999; 70: 836–7
Koller EA, Doraiswamy PM. Olanzapine-associated diabetes mellitus. Pharmacotherapy 2002; 22: 841–52
Novartis Pharmaceuticals product information: Clozaril (clozapine). Physician’s desk reference. 55th ed. Montvale (NJ): Medical Economics Company, Inc., 2001: 2155–9
Taylor D. Pharmacokinetic interactions involving clozapine. Br J Psychiatry 1997; 171: 109–12
Walker AM, Lanza LL, Arellano F, et al. Mortality in current and former users of clozapine. Epidemiology 1997; 8: 671–7
Litovitz TL, Klein-Schwartz W, Dyer KS, et al. 1997 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1998; 16: 443–97
Litovitz TL, Klein-Schwartz W, White S, et al. 2000 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001; 19: 337–95
Hoehns JD, Fouts MM, Kelly MW, et al. Sudden cardiac death with clozapine and sertraline combination. Ann Pharmacother 2001; 35: 862–6
Litovitz TL, Klein-Schwartz W, Caravati EM, et al. 1998 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1999; 17: 435–87
Meeker JE, Herrmann PW, Som CW, et al. Clozapine tissue concentrations following an apparent suicidal overdose of Clozaril. J Anal Toxicol 1992; 16: 54–6
Keller T, Miki A, Binda S, et al. Fatal overdose of clozapine. Forensic Sci Int 1997; 86: 119–25
Springfield AC, Bodiford E. An overdose of risperidone. J Anal Toxicol 1996; 20: 1580–4
Wyderski RJ, Starrett WG, Abou-Saif A. Fatal status epilepticus associated with olanzapine therapy. Ann Pharmacother 1999; 33: 787–9
Czekalla J, Kollack-Walker S, Beasley CM. Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry 2001; 62 Suppl. 2: 35–40
Jenkins AJ, Sarconi KM, Raaf HN. Determination of olanzapine in a postmortem case. J Anal Toxicol 1998; 22: 605–9
Elian AA. Fatal overdose of olanzapine. Forensic Sci Int 1998; 91: 231–5
Merrick TC, Felo JA, Jenkins AJ. Tissue distribution of olanzapine in a postmortem case. Am J Forensic Med Pathol 2001; 22: 270–4
Stephens BG, Coleman DE, Baselt RC. Olanzapine-related fatality. J Forensic Sci 1998; 43: 1252–3
Gerber JE, Cawthon B. Overdose and death with olanzapine: two case reports. Am J Forensic Med Pathol 2000; 21: 249–51
Anderson DT, Fritz KL. Quetiapine (Seroquel) concentrations in seven postmortem cases. J Anal Toxicol 2000; 24: 300–4
Modai I, Hirshmann S, Rava A, et al. Sudden death in patient’s receiving clozapine treatment: a preliminary investigation. J Clin Psychopharmacol 2000; 20: 325–7
Idanpaan-Heikkila J, Alhava E, Olkinuora M, et al. Agranulocytosis during treatment with clozapine. Eur J Clin Pharmacol 1977; 11: 193–8
Honigfeld G, Arellano F, Sethi, et al. Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril national registry. J Clin Psychiatry 1998; 59Suppl. 3: 3–7
Honigfeld G. Effects of the clozapine national registry system on incidence of deaths related to agranulocytosis. Psychiatr Serv 1996; 47: 52–6
Alphs LD, Anand R. Clozapine: the commitment to patient safety. J Clin Psychiatry 1999; 60 Suppl. 12: 39–42
Hagg S, Spigset O, Bate A, et al. Myocarditis related to clozapine treatment. J Clin Psychopharmacol 2001; 21: 382–8
Kilian JG, Kerr K, Lawrence C, et al. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999; 354: 1841–5
Devarajan S, Kutcher SP, Dursun SM. Clozapine and sudden death [letter]. Lancet 2000; 355: 841
Chan NN. Clozapine and sudden death [letter]. Lancet 2000; 355: 842
Koren W, Kreis Y, Duchowiczny K, et al. Lactic acidosis and fatal myocardial failure due to clozapine. Ann Pharmacother 1997; 31: 168–70
Henderson DC. Clozapine: diabetes mellitus, weight gain, and lipid abnormalities. J Clin Psychiatry 2001; 62 Suppl. 23: 39–44
Avram AM, Patel V, Taylor HC, et al. Euglycemic clamp study in clozapine-induced diabetic ketoacidosis. Ann Pharmacother 2001; 35: 1381–7
Newcomer JW. Metabolic disturbances associated with anti-psychotic use. J Clin Psychiatry 2001; 62 Suppl. 27: 3–4, discussion 40-41
Colli A, Cocciolo M, Francobandiera G, et al. Diabetic ketoacidosis associated with clozapine treatment. Diabetes Care 1999; 22(1): 176–7
Koval MS, Rames LJ, Christie S, et al. Diabetic ketoacidosis associated with clozapine treatment. Am J Psychiatry 1994; 151: 1520–1
Smith H, Kenney-Herbert J, Knowles L. Clozapine-induced diabetic ketoacidosis. Aust N Z J Psychiatry 1999; 33: 120–1
Ai D, Roper TA, Riley JA. Diabetic ketoacidosis and clozapine. Postgrad Med J 1998; 74: 493–4
MacFarlane B, Davies S, Mannan K, et al. Fatal acute fulminant liver failure due to clozapine: a case report and review of clozapine-induced hepatotoxicity. Gastroenterology 1997; 112: 1707–9
Shammi CM, Remington G. Clozapine-induced necrotizing colitis. J Clin Psychopharmacol 1997; 17: 230–1
Levin TT, Barrett J, Mendelowitz A. Death from clozapine-induced constipation. Psychosomatics 2002; 43: 71–3
Hayes G, Gibier B. Clozapine-induced constipation [letter]. Am J Psychiatry 1995; 152: 298
Fuller MA, Sajatovic M. Drug information for mental health 2001. Hudson (OH): Lexi-Comp, Inc., 2001: 161–3
Laposata M. Assessment of ethanol intake: current tests and new assays on the horizon. Am J Clin Pathol 1999; 112: 443–50
Gillespie JA. Comment: sudden cardiac death with clozapine and sertraline combination [letter]. Ann Pharmacother 2001; 35: 1671
Litovitz TL, Klein-Schwartz W, White S, et al. 1999 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2000; 18: 517–74
Fucci N, Romano B, Zirilli A. Acute intoxication with orphenadrine and clozapine. Forensic Sci Int 2001; 123: 13–6
Caccia S. Biotransformation of post-clozapine antipsychotics: pharmacological implications. Clin Pharmacokinet 2000; 38: 393–414
Fang J, Bourin M, Baker GB. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol 1999; 359: 147–51
Litovitz TL, Smilkstein M, Felberg L, et al. 1996 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1997; 15: 447–500
Ravin DS, Levenson JW. Fatal cardiac event following initiation of risperidone therapy. Ann Pharmacother 1997; 31: 867–70
Owens DGC. Extrapyramidal side effects and tolerability of risperidone: a review. J Clin Psychiatry 1994; 55(5 Suppl.): 29–35
Kern JL, Cernek PK. Delayed risperidone-induced neuroleptic malignant syndrome [letter]. Ann Pharmacother 1996; 30: 300
Sitarz WE. Comment: delayed risperidone-induced neuroleptic malignant syndrome [letter]. Ann Pharmacother 1996; 30: 1342–3
Croarkin PE, Jacobs KM, Bain BK. Diabetic ketoacidosis associated with risperidone treatment. Psychosomatics 2000; 41: 369–70
Haupt DW, Newcomer JW. Risperidone-associated diabetic ketoacidosis. Psychosomatics 2001; 42: 279–80
Acri AA, Henretig FM. Effects of risperidone in overdose. Am J Emerg Med 1998; 16: 498–501
Callaghan JT, Bergstrom RF, Ptak LR, et al. Olanzapine: pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 1999; 37: 177–93
Ragucci KR, Wells BJ. Olanzapine-induced diabetic ketoacidosis. Ann Pharmacother 2001; 35: 1556–8
Lindenmayer JP, Patel R. Olanzapine-induced ketoacidosis with diabetes mellitus [letter]. Am J Psychiatry 1999; 156: 1471
Goldstein LE, Sporn J, Brown S, et al. New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment. Psychosomatics 1999; 40: 438–43
Gatta B, Rigalleau V, Gin H. Diabetic ketoacidosis with olanzapine treatment. Diabetes Care 1999; 22: 1002–3
Selva KA, Scott SM. Diabetic ketoacidosis associated with olanzapine in an adolescent patient. J Pediatr 2001; 138: 936–8
Doucette DE, Grenier S, Robertson PS. Olanzapine-induced acute pancreatitis. Ann Pharmacother 2000; 34: 1128–31
Eli Lilly Industries product information: Zyprexa (olanzapine). Physicians’ desk reference. 55th ed. Montvale (NJ): MedicalEconomics Company, 2001: 1788–93
Lee JW, Crismon ML, Dorson PG. Seizure associated with olanzapine. Ann Pharmacother 1999; 33: 554–6
Woolley J, Smith S. Lowered seizure threshold on olanzapine. Br J Psychiatry 2001; 178: 85–6
Zeeca Pharmaceuticals product information: Seroquel (quetiapine). Physician’s desk reference. 55th ed. Montvale (NJ): Medical Economics Company, 2001: 639–43
Sobel M, Jaggers ED, Franz MA. New-onset diabetes mellitus associated with the initiation of quetiapine treatment. J Clin Psychiatry 1999; 60: 556–7
Ripple MG, Pestaner JP, Levine BS, et al. Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol 2000; 21: 370–4
Harmon TJ, Benitez JG, Krenzelok EP, et al. Loss of consciousness from acute quetiapine overdosage. Clin Toxicol 1998; 36: 599–602
Pollak PT, Zbuk K. Quetiapine fumarate overdose: clinical and pharmacokinetic lessons from extreme conditions. Clin Pharmacol Ther 2000; 68: 92–7
Tandon R, Harrigan E, Zorn SH. Ziprasidone: a novel anti-psychotic with unique pharmacology and therapeutic potential. J Serotonin Res 1997; 4: 159–77
Pfizer Roerig product information: Geodon (ziprasidone). Physicians’ desk reference. 56th ed. Montvale (NJ): Medical Economics Company, 2002: 2688–92
Davis R, Markham A. Ziprasidone. CNS Drugs 1997; 8: 153–9
Glassman AH, Bigger JT. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001; 158: 1774–82
Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation,torsade de pointes and sudden death. Drugs 2002; 62: 1649–71
Taylor DM. Prolongation of QTc interval and antipsychotics [letter]. Am J Psychiatry 2002; 159: 1062
Miceli JJ, Smith M, Robarge L. The effects of ketoconazole on ziprasidone pharmacokinetics: a placebo-controlled crossover study in healthy volunteers. Br J Clin Pharmacol 2000; 49Suppl. 1: 71S–6S
Burton S, Heslop K, Harrison K, et al. Ziprasidone overdose [letter]. Am J Psychiatry 2000; 157: 835
House M. Overdose of ziprasidone. Am J Psychiatry 2002; 159: 1061–2
American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. Position statement: single-dose activated charcoal. J Toxicol Clin Toxicol 1997; 35: 721–41
Lewin NA. Neuroleptic agents. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al., editors. Goldfrank’s toxicologic emergencies. 6th ed. Stamford (CT): Appleton and Lange, 1998: 943–53
Burns MJ, Linden CH, Graudins A, et al. A comparison of physostigmine and benzodiazepines for the treatment of anti-cholinergic poisoning. Ann Emerg Med 2000; 35: 374–81
Lee HS, Tan CH, Au L, et al. Serum and urine risperidone concentrations in an acute overdose. J Clin Psychopharmacol 1997; 17: 325–6
Janssen Pharmaceuticals product information: Risperidal (risperidone). Physicians’ desk reference. 55th ed. Montvale (NJ): Medical Economics Company, 2000: 1453–7
Pinninti NR, DeLeon J. Interaction of sertraline with clozapine [letter]. J Clin Psychopharmacol 1997; 17: 119–20
Good MI. Lethal interaction of clozapine and buspirone [letter]. Am J Psychiatry 1997; 154: 1472–3
Khan AY, Preskorn SH. Increase in plasma levels of clozapine and norclozapine after administration of nefazodone [letter]. J Clin Psychiatry 2001; 62: 375–6
Raaska K, Neuvonen PJ. Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia. Eur J Clin Pharmacol 2000; 56: 585–9
Markowitz JS, Gill HS, Devane CL, et al. Fluoroquinolone inhibition of clozapine metabolism [letter]. Am J Psychiatry 1997; 154: 881
Joos A, Frank UG, Kaschka WP. Pharmacokinetic interaction of clozapine and rifampicin in a forensic patient with an atypical mycobacterial infection. J Clin Psychopharmacol 1998; 18: 83–5
Abraham G, Grunberg B, Gratz S. Possible interaction of clozapine and lisinopril [letter]. Am J Psychiatry 2001; 158: 969
Gomberg RF. Interaction between olanzapine and haloperidol [letter]. J Clin Psychopharmacol 1999; 19: 272–3
Deshauer D, Albuquerque J, Alda M, et al. Seizures caused by possible interaction between olanzapine and clomipramine [letter]. J Clin Psychopharmocol 2000; 20: 283–4
Markowitz JS, DeVane CL. Suspected ciprofloxacin inhibition of olanzapine resulting in increased plasma concentration [letter]. J Clin Psychopharmacol 1999; 19: 289–91
Licht RW, Olesen OV, Friis P, et al. Olanzapine serum concentrations lowered by concomitant treatment with carbamazepine [letter]. J Clin Psychopharmacol 2000; 20: 110–2
Dev V, Raniwalla J. Quetiapine: a review of its safety in the management of schizophrenia. Drug Saf 2000; 23: 295–307
Nudelman E, Vinuela LM, Cohen CI. Safety in overdose of quetiapine: a case report [letter]. J Clin Psychiatry 1998; 59: 433
Van Wattum PJ. Valproic acid and risperidone. J Am Acad Child Adolesc Psychiatry 2001; 40: 866–7
Wong YW, Yeh C, Thyrum PT. The effects of concomitant phenytoin administration on the steady-state pharmacokinetics of quetiapine. J Clin Psychopharmacol 2001; 21: 89–93
Acknowledgements
The authors have no potential conflicts of interest, and no funding was received for the development of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Trenton, A.J., Currier, G.W. & Zwemer, F.L. Fatalities Associated with Therapeutic Use and Overdose of Atypical Antipsychotics. CNS Drugs 17, 307–324 (2003). https://doi.org/10.2165/00023210-200317050-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00023210-200317050-00002