A review of olanzapine-associated toxicity and fatality in overdose

Review Paper
Examen critique
A review of olanzapine-associated
toxicity and fatality in overdose
Pierre Chue, MB BCh; Peter Singer, BSc, PhD
Chue — Department of Psychiatry, University of Alberta and Alberta Hospitals; Singer — Office of the Chief MedicalExaminer, Edmonton, Alta.
Objective: Given the increasing use of atypical antipsychotics in psychiatric populations and the very lim-
ited data concerning the safety of such drugs, we examined the available data on olanzapine in untreated
overdose situations. Methods: Available toxicity data concerning olanzapine were obtained from the
Offices of the Medical Examiners of Canada, the Canadian Adverse Drug Reaction Monitoring Program and
a review of the literature. Results: Despite the complexities and limitations of postmortem data analysis,
29 deaths were identified where an overdose of olanzapine was either the principal cause of toxicity or a
significant contributor in combined toxicity. Conclusions: Olanzapine is associated with toxicity in certain
overdose situations, but evidence of any relation is limited and likely influenced by the higher rates of car-
diovascular disease and sudden death in subjects with schizophrenia. Recommendations: Similar toxicity
data reviews should be conducted for all commonly prescribed psychotropics. Early signal detection and
effective notification processes are crucial in the event that serious adverse effects do occur.
Objectif : Compte tenu de l’utilisation accrue des neuroleptiques atypiques chez les patients en psychiatrie
et de la somme très limitée de données au sujet de l’innocuité de ces médicaments, nous avons examiné les
données disponibles sur l’olanzapine dans des cas de surdose non traitée. Méthodes : Les données
disponibles sur la toxicité de l’olanzapine ont été recueillies auprès de cabinets d’examinateurs médicaux au
Canada et du Programme canadien de surveillance des effets indésirables des médicaments, ainsi qu’au
moyen d’un examen de la littérature scientifique. Résultats : Malgré la complexité et les limites de
l’analyse des données après le décès, on est parvenu à établir que dans 29 décès, une surdose d’olanzapine
était soit la principale cause de toxicité, soit un facteur contribuant considérablement à une toxicité mixte.
Conclusions : Dans certains cas de surdose, l’olanzapine est associée à la toxicité, mais on ne peut établir
avec certitude cette association, car les taux plus élevés de maladie cardiovasculaire et de mort subite chez
les sujets atteints de schizophrénie influent probablement sur les données. Recommandations : Il faudrait
effectuer d’autres examens semblables s’attachant aux données sur la toxicité de tous les psychotropes
fréquemment prescrits. Lorsque des effets indésirables graves se produisent, il est essentiel de détecter
rapidement les signaux et de prendre des mesures efficaces de notification.
Correspondence to: Dr. Pierre Chue, 3rd Floor, 9942-108 St., Edmonton AB T5K 2J5; fax 780 425-9317; pchue@ualberta.ca
Medical subject headings: adverse drug reaction reporting systems; antipsychotic agents; drug toxicity; olanzapine; overdose; suicide.
J Psychiatry Neurosci 2003;28(4):253-61.
Submitted Apr. 25, 2002Revised Nov. 20, 2002Accepted Jan. 14, 2003 J Psychiatry Neurosci 2003;28(4)
Introduction
using the keywords atypical antipsychotics, drug toxicity,olanzapine and overdose. All cases involving positive Olanzapine is an atypical antipsychotic of the thienoben- toxicology for olanzapine (including deaths ascribed to zodiazepine class. Although structurally and function- other causes) investigated by the medical examiner of ally related to clozapine, it possesses a more favourable Alberta were reviewed. All of the Canadian medical side-effect profile.1,2 The symptoms in overdose are gen- examiners and the Health Product Safety Information erally a reflection of olanzapine’s known pharmacolog- Division of the Canadian Adverse Drug Reaction Mon- ical actions and encompass somnolence, mydriasis, itoring Program were contacted for information con- blurred vision, respiratory depression, hypotension and cerning similar cases reported in Canada from Septem- extrapyramidal and anticholinergic effects.3–6 Treated overdoses of up to 800 mg of olanzapine In Canadian jurisdictions, toxicology screening de- have been associated with blood (serum) concentra- pends on the type of death; it is usual in cases of sus- tions of up to 991 ng/mL and have included symptoms pected drug overdose or drug abuse. Time from death such as central nervous system depression, tachycar- to discovery is variable and may be unknown. Autopsy dia, hyperpyrexia, leukocytosis, elevated creatine phos- or external examination takes place as soon after death phokinase levels and paradoxical miosis mimicking as possible (generally same or next day) but may be opioid or α -agonist intoxication.6–11 delayed over weekends and in isolated instances. If Olanzapine overdoses in children are generally as- examination is delayed, the body is refrigerated as sociated with more significant adverse effects.3,8,12–17 soon as possible. Specimens taken at examination are Children therefore require more active intervention also refrigerated immediately. Postmortem blood is than adults. Olanzapine blood concentrations have generally not frozen because freezing breaks up cells, been reported to be as high as 472 ng/mL (observed in and this interferes with the analysis. Thus, blood is op- an infant who survived after ingesting 10 tablets).18 timally refrigerated at 4°C. Whole blood is used; the Although the usual dose range for olanzapine is blood is not centrifuged because postmortem blood is 5–15 mg/d, there are no standard reference values generally hemolysed and does not separate well into with respect to the expected concentrations of olanza- cells and serum. Screening usually takes place within pine after therapeutic administration. In clinical stud- 2 days and determination of positive cases within 1 or ies, steady state blood (plasma) concentrations of 2 weeks. Analysis takes place immediately after extrac- olanzapine are rarely over 150 ng/mL,19 but the poten- tion. Olanzapine is unstable in blood specimens, and tial for toxicity has been suggested at concentrations as because drug levels in liver are generally much higher low as 100 ng/mL.20 However, it should be noted that and less susceptible to postmortem change, they are toxicologic analysis of olanzapine is complicated by tissue redistribution after death, which leads to higher The analysis methods used in the Toxicology Labora- concentrations in postmortem blood samples; but con- tory of the medical examiner of Alberta are as follows versely, olanzapine’s instability in blood leads to lower (similar principles are employed in other toxicology concentrations in postmortem blood samples subjected For the quantitative analysis, postmortem blood, liver A presentation at the 47th Annual Meeting of the homogenate or diluted gastric contents (1 mL) were Society of Forensic Scientists in Ottawa, Nov. 3–5, 2000, first made basic with borate buffer (pH = 12, 2 mL, vor- on the frequency of detection of olanzapine in deaths tex). Internal standard was added (clozapine was used investigated by the medical examiner of Alberta stimu- as internal standard for olanzapine quantification until lated authors to further analyze the available toxicity replaced by analog LY170222). The basified specimen was then extracted with 1-chlorobutane (8 mL). Theorganic fraction was extracted with dilute sulphuric acid (3 mL, 0.1 N) and discarded. The aqueous acidlayer was retained and neutralized with sodium A comprehensive literature search of databases includ- hydroxide (0.5 mL, 2 N), and olanzapine and internal ing, but not limited to, MEDLINE, EMBASE and Inter- standard were re-extracted with 1-chlorobutane. The national Pharmaceutical Abstracts, was conducted chlorobutane was separated, concentrated under nitro- Rev Psychiatr Neurosci 2003;28(4)
Toxicity and fatality in olanzapine overdose gen and injected onto the gas chromatograph (GC) with GC and for acidic, neutral and basic solvent extracts by nitrogen–phosphorus detection (NPD). The same GC with NPD, electron capture detection (ECD) and process was used for sheep blood-based calibrators and mass spectroscopic detection (MSD). Olanzapine was controls. All chemicals were reagent grade or better, detected by GC/NPD and GC/ECD and its identity and solvents were distilled in-glass.
confirmed with GC/MSD by comparison with an au- The oven temperature was ramped from 180°C to thentic standard. Other drugs that were detected were 300°C at 20°C/min, with the injector and detector tem- quantified as necessary by GC/NPD, GC/MSD or liq- peratures at 260°C and 300°C, respectively. The 5 or more point calibration curve was usually linear over therange 100–5000 ng/mL, with a typical correlation coef- ficient of r2 = 0.99 and a y-intercept of less than 0.05.
Specimens with concentrations exceeding this range Of the 29 toxicology cases with recorded olanzapine were diluted appropriately and re-analyzed. Assays us- levels, 11 were reported in the literature (Table 1), 15 ing clozapine as internal standard tended to give qua- by medical examiners (Table 2, Table 3) and 1 in the dratic rather than linear calibration curves, but with Canadian Adverse Drug Reaction Monitoring Pro- acceptable correlations (typically 0.997 with a y-intercept gramme (Table 3). In addition, 2 other cases from the of 0.1). Under these conditions, olanzapine eluted at literature were deemed relevant and are discussed, approximately 5.3 min and LY170222 at 5.5 min. Olanza- although no olanzapine levels were available.
pine extracts are unstable if exposed to air overnight and Elian21 and Stevens et al22 reported a case each (1, 2) were analyzed immediately after extraction.
involving the suicidal ingestion of 600 mg of olanzapine.
For the qualitative analysis, postmortem blood and Anderson and Kuwahara18 identified olanzapine in 35 urine specimens (when available) were screened by a cases where the cause of death was not immediately panel of immunoassays (ELISA, fluorescence polariza- apparent or a toxicology screen had been specifically re- tion immunoassay and radioimmunoassay); they were quested. In most cases, the cause of death was attributed screened for volatiles (including ethanol) by headspace to other drugs (including multiple drug intoxication), Table 1: Olanzapine toxicity cases from the literature
Note: F = female; M = male; Ht = heart; F blood = femoral blood.
*Blanks indicate data not recorded.
†Blood levels in ng/mL; gastric total contents in ng/mL; urine in ng/mL.
J Psychiatry Neurosci 2003;28(4)
the decedent’s actions or the circumstances involved.
attributed 2 deaths to olanzapine toxicity (9, 10); olanza- Heart and femoral blood olanzapine concentrations pine blood concentrations in the other 5 cases were ranged from 25 ng/mL to 4800 ng/mL and 25 ng/mL to between 40 ng/mL and 270 ng/mL, and urine concen- 1600 ng/mL, respectively. Although these levels were trations were between 190 ng/mL and 500 ng/mL. equal to or greater than accepted therapeutic levels, 2 Toxic Exposure Surveillance System (TESS) data are cases (3, 4) specifically indicated olanzapine toxicity.
compiled by the American Association of Poison Con- Of 11 deaths ascribed to natural causes, significant car- trol Centers in conjunction with most US poison control diovascular disease was noted in 8 (age range 22–32 yr).
centres. In their 1998 annual report, 7 fatal exposures Gerber and Cawthon23 attributed 2 deaths to olanzapine involving olanzapine were described (6 from acute in a 5-month period from December 1997 — 1 was a sui- intentional overdose);25 3 cases appeared to involve cide (5) and the other believed to be due to direct toxic- olanzapine alone, but blood levels were available in 1 ity in a 38-year-old man (6) who had been taking 30 mg case only (11). Of the other 2 cases, 1 was a 38-year-old
olanzapine daily for 8 months before he died (autopsy man who died, despite active intervention, of cerebral findings included coronary artery disease and a non- hemorrhage with hypotension and hyperpyrexia; blood significant blood concentration of risperidone). Robert- results included hyperglycemia, hypokalemia and son and McMullin20 analyzed 58 postmortem whole elevated creatine phosphokinase. No details were avail- blood specimens (for most, the cause and manner of able on the other case attributed to olanzapine toxicity death were unknown); olanzapine concentrations (these 2 cases are included in the total). Of the TESS cases involving coingestants, 1 was a 35- 358 ng/mL, median 130 ng/mL). Two deaths were at- year-old man who was taking olanzapine 10 mg twice tributed to olanzapine toxicity — 1 was a 43-year-old daily and developed hyperpyrexia, refractory hypo- man with a history of seizure disorder (7) and the other tension and bleeding after taking a 20-mg paroxetine (believed to be direct toxicity) was a 20-year-old man tablet; he died despite intervention. Wong et al26 re- purportedly taking 70 mg of olanzapine daily (8). Of 7 ported 5 cases in which cause of death was ascribed to cases investigated in a 5-month period, Levine et al24 pulmonary embolus, arteriosclerotic heart disease, Table 2: Olanzapine toxicity cases from the medical examiner of Alberta
Note: M = male; F = female; Ht = heart; F blood = femoral blood; IVC = inferior vena cava; Cent = central.
*Blood levels in ng/mL; liver levels in ng/g; gastric total contents in ng/mL.
Rev Psychiatr Neurosci 2003;28(4)
Toxicity and fatality in olanzapine overdose injuries due to suicide and undetermined sudden in which olanzapine was the only drug detected, but death (2 cases). All cases involved other coingestants, death was due to diabetic ketoacidosis, and another and olanzapine blood concentrations ranged from case in which death was due to atherosclerotic coro- nary artery disease. Five cases may also have involved Thus, a total of 13 deaths in which olanzapine ap- excess or an overdose of olanzapine (olanzapine blood peared to significantly contribute, either in combined concentrations 170–1540 ng/mL, liver concentrations toxicity or as the principal cause of toxicity, were identi- 2500–4900 ng/g), but the primary toxicity was ethanol plus other drugs. Blood concentrations of olanzapine in Of the 27 cases from the Alberta medical examiner in the remaining 16 cases ranged from 85 ng/mL to which olanzapine was detected, 6 were attributed to 490 ng/mL (mean 260 ng/mL). Five of those examined olanzapine toxicity. In cases 12, 13 and 14, the high were found to have significant atherosclerosis, which concentrations of concomitant drugs suggested acute was determined to be the cause of death. One case combined toxicity, but in cases 15, 16 and 17, olanza- involved hypertension, and 2 of those who died had pine was the primary intoxicant (olanzapine blood con- centrations of 1170, 970, 660, 1700, 4410 and 2000 ng/mL Of the 12 Canadian medical examiners contacted, 4 [mean 1810 ng/mL] and liver concentrations of 13 000, (Quebec, Manitoba, Yukon, British Columbia) pro- 18 000, 24 000, 27 000, 47 000 and 5600 ng/g [mean vided 9 cases (18–26). Saskatchewan records drug over- 30 800 ng/g], respectively). In the other cases, drugs dose as cause of death but not the offending drug; other than olanzapine predominated, except for 1 case Nova Scotia does not have a computerized database; Table 3: Olanzapine toxicity cases from medical examiners in British Columbia, Manitoba, Quebec and
Yukon and from the Canadian Adverse Drug Reaction Monitoring Program
myocardial infarction, diabetes,cerebral arteriosclerosis andolanzapine toxicity N-desalkylflurazepam2-OH-ethylflurazepamMetoclopromideEthanol Note: M = male; F = female; Ht = heart.
*Blood levels in ng/mL; liver levels in ng/g; gastric total contents in ng/mL; spleen levels in ng/mL.
J Psychiatry Neurosci 2003;28(4)
Newfoundland and Prince Edward Island had no cases bers of possible drug-related toxicity cases.
on record. Six cases (18–23) involved concomitant The findings have clinical relevance, but the signifi- drugs; in 3 cases, olanzapine (24–26) was the only cance, particularly for olanzapine, is unclear given the drug. Cardiovascular disease and diabetes were re- lack of comparative data at this point. The inherent ported in 1 case (19), and obesity, asthma and breast difficulties in collecting these data include lack of com- carcinoma were reported in 1 case (20).
puterized databases, toxicology findings not systema- The Canadian Adverse Drug Reaction Monitoring tically recorded by drug, and cause of death not Program Newsletter of July 200027 advised that olanza- recorded as an overdose. Interpretation of postmortem pine was reported as a suspected drug in 22 deaths, concentrations of new drugs is particularly difficult be- including 8 involving suicide or overdose and 14 due cause no postmortem database exists and perimortem to a variety of causes (e.g., neuroleptic malignant syn- details are usually unavailable. Postmortem concentra- drome, arrhythmia, myocardial infarction, heart failure tions are usually compared with therapeutic or phar- and pneumonia, sepsis, sudden death, mesenteric macokinetic data because this is the only information thrombosis, choking and unknown). Of the overdose available and, consequently, high concentrations are cases, 1 was previously reported (25), 1 was attributed interpreted as consistent with overdose. Furthermore, to primary olanzapine toxicity (27) (blood concentra- the number of cases detected is not only a function of tion 520 ng/mL) and 1 was due to combined bupro- the frequency of drug use in that particular jurisdiction pion and fluoxetine toxicity, also previously reported but also of the analytical procedures used by the in- (12). Malignant hyperpyrexia was reported as the vestigating laboratory. Thus, clozapine, olanzapine and cause of death in an overdose of olanzapine (150 mg) quetiapine are readily detected by standard screening and diphenhydramine (20 mg). The cause of death was techniques (GC/MSD but not immunoassay) and can not determined in 1 case in which olanzapine was therefore be quantified where indicated. However, added to an existing regimen of loxapine, nor in 1 case risperidone and pimozide are not detected by the of a patient with hypertension, chronic obstructive pul- screening procedures used in most postmortem toxi- monary disease, adrenal insufficiency and irritable cology laboratories, and their overdose occurrence is bowel syndrome (with a 34-kg weight gain in 2 years) The relative safety of the atypical antipsychotics has Of note, all information provided by the Health been comprehensively reviewed elsewhere.28 In a study Product Safety Information Division is subject to the of elderly patients, Nasrallah et al29 found a lower mor- caveat that data are unpublished and received from a tality rate with atypical antipsychotic use (4.8%) than variety of sources; thus, cause and effect relations have with haloperidol (21.4%) over a 2-year period. Also, a review of 574 inquiries to the UK National Poisons In- From medical examiners’ reports and the Canadian formation Service over 9 months revealed no fatalities Adverse Drug Reaction Monitoring Program, there after overdoses of atypical antipsychotics.30 The authors were 16 cases in which olanzapine was identified as concluded that olanzapine and risperidone had a more the principal cause of toxicity or contributory in com- favourable overdose profile than clozapine or sulpiride, and that monitoring poisons centre inquiries was a use-ful way of comparing overdose toxicities. However, the Discussion
outcome of treated overdoses in hospital settings likelydiffers from outcomes for individuals who do not re- Given the limitations of autopsy material, a causal ceive active intervention, and, as the authors comment, relation cannot be inferred from the data presented.
patients who die outside of hospital are unlikely to be Nonetheless, there are potentially 29 cases in which revealed by inquiries to a poison centre.30 acute olanzapine toxicity appears to have contributed Early administration of activated charcoal may to death. These numbers are definitely small when decrease the oral bioavailability of olanzapine by compared with the number of prescriptions for olanza- 50%–60%. Gardner et al31 reported rapid recovery with pine, but it is likely that data for many cases (not just the use of activated charcoal in a 29-year-old woman involving olanzapine) are not readily accessible and from an overdose of 1110 mg of olanzapine that was therefore represent underestimates of the total num- associated with initial tachypnea, tachycardia, unstable Rev Psychiatr Neurosci 2003;28(4)
Toxicity and fatality in olanzapine overdose blood pressure and hypoxemia. The findings of this suggested a minimum effective therapeutic blood review suggest an adverse outcome for patients (often (plasma) concentration of 9–10 ng/mL35,36 and a thera- with pre-existing undetected physical pathology such peutic range of 9–23 ng/mL.37 However, others report a as cardiovascular disease) who take overdoses of mul- significantly higher range of values in clinical practice.
tiple medications and do not receive intervention.
An analysis of 1653 clinical blood (serum) samples Olanzapine has a high volume of distribution (i.e., found olanzapine concentrations to range from 3 ng/mL 10–20 L/kg), and liver levels are significantly higher to 390 ng/mL, with 86% of samples between 5 ng/mL than blood levels. After death, significant redistribu- and 75 ng/mL (mean 36 ng/mL, median 26 ng/mL).20 tion from liver to central blood specimens occurs, and Similarly, Xue et al38 proposed a therapeutic range of the higher range of olanzapine concentrations in post- 5–75 ng/mL on the basis of 231 patient blood (serum) mortem blood is consistently observed independent of samples in which 90% of values fell within this range any assay differences. Higher concentrations are also (mean 33 ng/mL, median 28 ng/mL). An even wider observed in central (heart) blood specimens than in range (< 5–103 ng/mL) was detected in 369 samples peripheral (femoral) blood specimens.18 Tissue redistri- obtained from 173 inpatients taking 5–30 mg/d, and bution after death has been demonstrated for tricyclic levels were found to be highly variable between indi- antidepressants and antipsychotics;32,33 consequently, in viduals (dosing regimens and time of collection rela- many postmortem situations, liver concentrations are a tive to time of ingestion were not recorded).36 The rate of metabolism of olanzapine can vary up to Postmortem olanzapine blood concentrations may 20-fold among individuals, and because of extensive not represent true antemortem or perimortem levels first-pass metabolism (up to 40%), large overdoses re- and should be interpreted cautiously. In only 1 case of sult in nonlinear pharmacokinetics leading to signifi- our series (17) was an antemortem specimen available cant increases in blood concentrations.7 Hiemke et al36 for comparison. The patient died approximately 2 found olanzapine blood (serum) concentrations were hours after admission to hospital, and the postmortem increased 3-fold and 2-fold with doses of 5 mg/d and olanzapine heart blood concentration was elevated 5- 20 mg/d, respectively, when olanzapine was combined fold over the antemortem level. Although most olanza- with fluvoxamine, suggesting a competitive inhibition pine-related deaths involve multiple concomitant drug effect. Olanzapine is extensively metabolized in the ingestion and other physical risk factors, death due pri- liver,39 and an impairment of enzyme-mediated metab- marily to olanzapine toxicity has been suggested at olism may lead to variable blood concentrations. How- concentrations as low as 100 ng/mL.20 The stability of ever, the existence of multiple pathways for olanzapine olanzapine in postmortem blood during storage metabolism suggests that an alteration of one route of should be considered because blood concentrations metabolism may not necessarily result in significant have been found to decrease by 23%–84% from their change in the clearance of olanzapine in vivo. In many original levels during storage.18,24 This suggests that de- overdose situations, there is often limited information pendent upon time of analysis, olanzapine levels may concerning concomitant medications that were recently have been even higher at the time of death. Thus, be- prescribed but not necessarily taken at the time of over- cause of olanzapine’s instability in blood, sample con- dose. Furthermore, in clinical practice, antipsychotics centrations should be measured as soon as possible are frequently taken in conjunction with other drugs after death. Compounds with a heterocyclic sulfur and at greater than recommended doses.
atom, such as chlorpromazine and perphenazine, are Although the specific pathophysiology remains un- readily oxidized to sulfoxides and sulfones and are un- determined at this time, it has been suggested that the stable in liver homogenates;34 olanzapine may be simi- most likely mechanism of death in an overdose of olan- larly subject to in vitro degradation.
zapine involves cardiac toxicity at the cellular mem- The significant variation in blood concentrations of brane level.23 This would be consistent with the inferred olanzapine in clinical practice makes it difficult to in- nature and rapidity of the terminal event, but there are terpret postmortem findings. The average peak blood no data indicative of a direct cardiac toxicity with olan- (plasma) concentration was 11 ng/mL after a single zapine. Sudden death is more common in patients with oral dose of 12.2 mg,24 and it was 10 ng/mL after re- psychiatric problems, particularly those receiving anti- peated doses of 10 mg/d.21 A number of studies have psychotic drugs.40–44 A data mining study of the World J Psychiatry Neurosci 2003;28(4)
Health Organization database of adverse reactions de- P, Anton Saiz C, et al. The safety of olanzapine compared with tected a strong signal for an association between cloza- other antipsychotic drugs: results of an observational prospec-tive study in patients with schizophrenia (EFESO Study). J pine, cardiomyopathy and myocarditis44 and for an- Clin Psychiatry 2000;61:335-43.
tipsychotics as a group; but in fact, there were fewer Dougherty TJ, Greene TF, Farrell SE, Roberts JR. Adult and pedi- reports for olanzapine than for haloperidol or risperi- atric olanzapine overdose [abstract A165]. J Toxicol Clin Toxicol1997;35:550.
done. An analysis of 85 fatal intoxications found that 4. Dobrusin M, Lokshin P, Belmaker RH. Acute olanzapine over- pimozide and olanzapine were less likely to be associ- dose. Hum Psychopharmacol 1999;14:355-6.
ated with death in overdose than prothipendyl and 5. Schwartz JL. A new atypical antipsychotic. In: Schwartz JL, editor. Psychiatric times’ advances in psychopharmacology. Irvine chlorprothixene,45 which is surprising given pimozide’s known cardiotoxicity.46 Prolongation of the QT interval 6. Cohen LG, Fatalo A, Thompson BT, Bergeron GDC, Flood JG, may play a role in fatal arrhythmias, but olanzapine Poupolo PR. Olanzapine overdose with serum concentrations.
appears to have the least direct effect compared with 7. Bosch RF, Baumbach A, Bitzer M, Erley CM. Intoxication with risperidone, quetiapine or thioridazine.46 Cardiovascu- olanzapine. Am J Psychiatry 2000;157:304-5.
lar disease is an important risk factor for ischemic and 8. Powell G, Nelson L, Hoffman R. Overdose with olanzapine thrombotic vascular events as well as for QT prolonga- (Zyprexa), a new antipsychotic agent [abstract A166]. J ToxicolClin Toxicol 1997;35:550.
tion, and the increased prevalence of coronary artery 9. O’Malley GF, Sifert S, Heard K, Daly F, Dart RC. Olanzapine disease in patients with schizophrenia42,47 may be rele- overdose mimicking opioid intoxication. Ann Emerg Med 1999; vant in the context of elevated psychotropic drug con- 10. O’Malley GF, Sifert S, Heard K, Yip L. Pupillary effects of centrations after overdose. Similarly, diabetes mellitus olanzapine overdose mimic opiate and alpha-2 agonists and obesity (both additional risk factors for cardiovas- [abstract]. J Toxicol Clin Toxicol 1998;36:523.
cular disease) are more prevalent in patients with 11. Fogel J, Diaz JE. Olanzapine overdose. Ann Emerg Med 1998; schizophrenia, and an increased risk of these disorders 12. Chambers RA, Caracansi AM, Weiss G. Olanzapine overdose has been reported in patients taking olanzapine.48–50 cause of acute extrapyramidal symptoms. Am J Psychiatry Finally, given the frequency of antipsychotic combina- tion therapy and psychotropic polypharmacy in clin- 13. Yip L, Graham K. Clinical effects of olanzapine in a 2½-year- old male [abstract A164]. J Toxicol Clin Toxicol 1997;35:549-50.
ical practice, the possibility of increased risk of toxicity 14. Yip L, Dart RC, Graham K. Olanzapine toxicity in a toddler when olanzapine is combined with other psychotropics [letter]. Pediatrics 1998;102:1494-5.
15. Catalano G, Cooper DS, Catalano MC, Butera AS. Olanzapine overdose in an 18-month-old child. J Child Adolesc Psychophar- In summary, although olanzapine has been asso- ciated with toxicity in certain overdose situations, evi- 16. Bonin MM, Burkhart KK. Olanzapine overdose in a 1-year-old dence of any direct relation remains limited. The ad- male. Pediatr Emerg Care 1999;15:266-7.
verse consequences of overdose are compounded in 17. Bond GR, Thompson JD. Olanzapine pediatric overdose. Ann psychiatric populations because of frequent, yet often 18. Anderson DT, Kuwahara T. Thirty-five case studies involving undiagnosed or untreated physical illnesses, complex postmortem tissue distribution of olanzapine (Zyprexa) [ab- polypharmacy with high doses of psychotropic drugs stract A95]. In: Spiehler V, editor. Proceedings of the 1998 JointSOFT/TIAFT International Meeting; 1998 Oct 5–9; Albuquerque and delayed or absent interventions. Infrequent, seri- (NM). Newport Beach (CA): International Association of ous adverse effects can occur, and early signal detec- Forensic Toxicologists and Centre of Behavioural and Forensic tion and effective notification processes are crucial 19. Zyprexa product monograph. Toronto: Eli Lilly Canada Inc.; when they do occur. It is recommended that similar toxicology data reviews be conducted for commonly 20. Robertson MD, McMullin MM. Olanzapine concentrations in clinical serum and postmortem blood specimens — when doestherapeutic become toxic? J Forensic Sci 2000;45:418-21.
Competing interests: None declared for Dr. Singer. Dr. Chue has
21. Elian AA. Fatal overdose of olanzapine. Forensic Sci Int received speaker’s fees and travel assistance from Organon, Janssen, Eli Lilly, Novaris, Pfizer, GlaxoSmithKline and AstraZeneca.
22. Stephens BG, Coleman DE, Baselt RC. Olanzapine-related fatality. J Forensic Sci 1998;43:1252-3.
23. Gerber JE, Cawthon B. Overdose and death with olanzapine.
References
Am J Forensic Med Pathol 2000;21:249-51.
24. Levine BS, Wu SC, Smialek JE. Olanzapine concentrations in Beasley CM. Safety of olanzapine. J Clin Psychiatry 1997;15:19-21.
forensic investigations [abstract A114]. In: Spiehler V, editor.
2. Gomez JC, Sacristan JA, Hernandez J, Breier A, Ruiz Carrasco Proceedings of the 1998 Joint SOFT/TIAFT International Meeting; Rev Psychiatr Neurosci 2003;28(4)
Toxicity and fatality in olanzapine overdose 1998 Oct 5–9; Albuquerque (NM). Newport Beach (CA): Inter- for new antipsychotics. J Clin Psychiatry 1996;57:12-5.
national Association of Forensic Toxicologists and Centre of 38. Xue L, Crookham SB, Diamond FX, Davis PJ, Reiber TM.
Behavioural and Forensic Toxicology. p. 114.
Development of a gas chromatographic method for the deter- 25. Litovitz TL, Klein-Schwartz W, Caravati EM, Youniss J, mination of olanzapine in human serum, and a report of pa- Crouch B, Lee S. 1998 annual report of the American Asso- tient values abstract 450]. Clin Chem 1998:44:A103. ciation of Poison Control Centers Toxic Exposure Surveillance 39. Prior T, Chue P, Tibbo P, Baker G. Drug metabolism and atyp- System. Am J Emerg Med 1999;17:435-87.
ical antipsychotics. Eur Neuropsychopharmacol 1999;9:301-9.
26. Wong SHY, Gock SB, Venuti SE, Stormo A, Greenbaum VJ, 40. Brown RP, Kocsis JH. Sudden death and antipsychotic drugs.
Biedrzycki LM, et al. Olanzapine associated deaths: a report of Hosp Community Psychiatry 1984;35:486-91.
five cases [abstract A97]. In: Spiehler V, editor. Proceedings of 41. Appleby L, Thomas S, Ferrier N, Lewis G, Shaw J, Amos T.
the 1998 Joint SOFT/TIAFT International Meeting; 1998 Oct 5–9; Sudden unexplained death in psychiatric in-patients. Br J Psy- Albuquerque (NM). Newport Beach (CA): International Asso- ciation of Forensic Toxicologists and Centre of Behavioural 42. Chute D, Grove C, Rajasekhara B, Smialek JE. Schizophrenia and sudden death: a medical examiner case study. Am J Med 27. Cadario B. Olanzapine (Zyprexa): suspected serious reactions.
Can Adverse Drug React Newsl 2000;10:2-3. 43. Ruschena D, Mullen PE, Burgess P, Cordner SM, Barry-Walsh 28. Burns MJ. The pharmacology and toxicology of atypical J, Drummer OH, et al. Sudden death in psychiatric patients. Br antipsychotic agents. Clin Toxicol 2001;399:1-14.
29. Nasrallah HA, White TR, Nasrallah AT. Lower mortality in Coulter DM, Bate A, Meyboom RHB, Lindquist M, Edwards IR.
geriatric patients receiving atypical antipsychotics compared Antipsychotic drugs and heart muscle disorder in international to haloperidol [abstract A183]. Biol Psychiatry 2001;49:525.
pharmacovigilance: data mining study. BMJ 2001;322:1207-9.
30. Capel MM, Colbridge MG, Henry JA. Overdose profiles of new 45. Schreinzer D, Frey R, Stimpfl T, Vycudilik W, Berzlanovich A, antipsychotic agents. Int J Neuropsychopharmacol 2000;3:51-4.
Kasper S. Different fatal toxicity of neuroleptics identified by 31. Gardner DM, Milliken J, Dursun SM. Olanzapine overdose.
autopsy. Eur Neuropsychopharmacol 2001;11:117-24.
Am J Psychiatry 1999;156:1118-9.
46. Welch R, Chue P. Atypical antipsychotics and QT change. J 32. Pounder DJ, Jones GR. Post-mortem drug distribution: a tox- Psychiatry Neurosci 2000;25:154-60.
icological nightmare. Forensic Sci Int 1990;45:253-63.
47. Curkendall SM, Jingping M, Jones JK, Glasser D. Increased Jones GR, Pounder DJ. Site dependence of drug concentrations cardiovascular disease in patients with schizophrenia. In: in postmortem blood — a case study. J Ann Toxicol 1987;1195: 154th Annual Meeting of the American Psychiatric Association; 2001 May 5–10; New Orleans. Washington: American Psychi- 34. Stevens HM. The stability of some drugs and poisons in putre- fying human liver tissues. J Forensic Soc 1984;24:577-89.
Liebzeit KA, Markowitz JS, Caley CF. New onset diabetes and 35. Perry BJ, Sanger T, Beasley C. Olanzapine serum concentra- atypical antipsychotics. Eur Neuropsychopharmacol 2001;11:25-32.
tions and clinical response in acutely ill patients. J Clin Psycho- 49. Osser DN, Najarian DM, Dufresne RL. Olanzapine increases weight and triglyceride levels. J Clin Psychiatry 1999;60:767-70.
36. Hiemke C, Gerek S, Weigmann H, Hartter S. Monitoring 50. Melkersson KI, Hulting AL, Brismer KE. Elevated levels of in- serum levels of olanzapine [abstract P.01.247]. Int J Neuropsy- sulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry 37. Ereshefsky L. Pharmacokinetics and drug interactions update J Psychiatry Neurosci 2003;28(4)

Source: http://www.k4p.com/publications/jpn/pg253.pdf