A systematic review of cardiovascular effects after atypical antipsychotic medication overdose

ReviewA systematic review of cardiovascular effects after atypical antipsychotic medication overdose☆Hock Heng Tan MBBS a,b,Jason Hoppe DO b,c,Kennon Heard MD b,c,⁎a Accident and Emergency Department,Changi General Hospital,SingHealth,Singaporeb Rocky Mountain Poison and Drug Center,Denver Health,Denver,CO,USAc Division of Emergency Medicine,Colorado Emergency Medicine Research Center,University of Colorado Denver School of Medicine,Denver,CO,USAReceived24March2008;revised16April2008;accepted18April2008Abstract As the use of atypical antipsychotic medications(AAPMs)increases,the number ofoverdoses continues to grow.Cardiovascular toxicity was common with older psychiatric medicationsbut seems uncommon with AAPM.We conducted a systematic literature review to describe thecardiovascular effects reported after overdose of5common AAPM:aripiprazole,olanzapine,quetiapine,risperidone,and ziprasidone.We included case reports and case series describing overdoseof these5medications identified in a search of MEDLINE,EMBASE,and abstracts from majortoxicology meetings.We found13pediatric cases(age,b7years),22adolescent cases(age,7-16years),and185adult cases.No pediatric case described a ventricular dysrhythmia or a cardiovasculardeath.In the adolescent and adult cases,we found numerous reports of prolonged corrected QTinterval and hypotension,but there were only3cases of ventricular dysrhythmia and3deaths that mayhave been due to direct cardiovascular toxicity.The results from case series reports were similar to thesingle case report data.Our review suggests that overdose of AAPM is unlikely to cause significantcardiovascular toxicity.©2009Elsevier Inc.All rights reserved.1.IntroductionAtypical antipsychotic medications(AAPMs)have lar-gely replaced the older antipsychotic medications(APMs)as the drug of choice for the management of psychotic patients. Overdose of these medications are common with more than 40000exposures reported to US Poison Centers in2006[1].The primary system affected by overdose of AAPM is the central nervous system[2].Sedation,which may progress to coma,is the primary concern.There is also considerable concern about the potential for cardiovascular toxicity.The most common cardiovascular effects are tachycardia, hypotension(usually mild),and prolongation of the corrected QT(QTc)interval.The prolongation of the QTc interval is concerning because this suggests that patients may be predisposed to torsade de pointes(TdP).However,it has been our experience that this event is rare if it occurs at all. The objective of this paper is to describe the reported cardiovascular effects that occur after acute overdose of the5 AAPM commonly used in the United States.☆Dr Heard was supported by DA620573.⁎Corresponding author.Rocky Mountain Poison and Drug Center, Denver,CO80204,USA.Tel.:+13037391264;fax:+13037391475.E-mail address:kennon.heard@(K.Heard)./locate/ajem2.MethodsThis was a systematic review of AAPM overdose reports identified through a search of the MEDLINE and EMBASE databases and several other sources detailed below.2.1.Search MethodsWe identified appropriate reports using MEDLINE (January1950to November1,2007)and EMBASE(January 1974to November1,2007)searches.The search terms included aripiprazole(keyword),olanzapine(keyword), risperidone(keyword or MesH heading),ziprasidone(key-word),and quetiapine(keyword).We elected to exclude clozapine from our search because it is rarely used clinically, and we also did not include paliperidone that has only been approved in the United States since December2006.To identify studies reporting overdose,we limited the identified articles to those with the keywords:overdose,poison, poisoning,or ingestion.These articles were then limited to human(subject).We excluded unpublished data,adverse effects during therapeutic use of AAPM,and laboratory and forensic articles that reported little clinical information.The following data sources were manually searched:The Annual Report of the American Association of Poison Control Centers from1994to2006,The North American Congress of Clinical Toxicology abstracts from1994to2007, and European Association of Poison Control Centers annual meeting abstracts from2002to2007.Manual bibliography search was also done on review articles and the articles that were identified during the MEDLINE and EMBASE search.2.2.Article reviewTwo authors evaluated the articles in English indepen-dently using a standardized data abstraction form.Non-English articles were evaluated by1reviewer fluent in the language.After review,the articles were separated into2 categories:(1)case level data and(2)case series that give summary data.Where sufficient clinical data from individual cases could be extracted from a case series(case level data), the results were included in the individual case reports section. We divided the reports into these groups because the case level data could provide details on possible confounders that would not be detected in summary data,whereas case series could provide a rough estimate of the incidence and spectrum of events that occurred.Cases where the patient did not have an overdose were excluded from the analysis.Patients who overdosed on2AAPM were included in the totals for both AAPM.Hence,the total number of cases analyzed may be more than the actual number of cases involved.Variables that were not available were recorded as“not reported,”and variables that the authors reported as normal (eg,vital signs and electrolytes)were recorded as“normal.”Reviewers abstracted the data into a Microsoft Excel spreadsheet using pull-down lists to assure consistent coding. All discrepancies were resolved by consensus.2.3.Variable definitionsWe defined an acute overdose as the ingestion of a dose greater than the maximum recommended single dose from the package insert.Patients who developed complications due to chronic therapy and who developed adverse reactions after a therapeutic first dose of the medication were not included in the analysis.We used the following definitions for outcomes in adults: QTc interval prolongation,greater than440milliseconds; tachycardia,heart rate(HR)of greater than100beats per minute(bpm);QRS interval prolongation,greater than100 milliseconds;and hypotension,systolic blood pressure of90 mm Hg or lesser.A QTc interval of500milliseconds or greater was considered significant QTc interval prolongation [3].We also recorded these findings as present if the author stated that they occurred without reporting numeric values. The reference values for pediatric age groups(up to12years of age)were defined from a standard textbook(Rosen's Principles and Practice of Emergency Medicine).Additional outcomes included the need for intubation,the need for vasopressor drugs,and the final outcome(recorded as death, recovery with deficits,or full recovery).We collected data on potential confounders such as coingestions,prior medications,preexisting heart disease,or electrolyte abnormalities.Hypokalemia was defined as serum potassium below3.5mEq/L;hypocalcemia,as total calcium below 4.2mEq/L;and hypomagnesemia,as magnesium below1.3mEq/L.These variables were recorded as present,not present,or not recorded.2.4.AnalysisAs the etiology of the exposure(accidental vs deliberate) and comorbidities differ among patients of different ages,we stratified our results by age group:younger than7years,7to 16years,and older than16years(adult).Descriptive statistics were calculated for case reports and case series with patient level data.Median and ranges are reported for continuous data,whereas percentages are reported for nominal data.3.Results3.1.SearchA total of135English and13non-English articles and reports were included in our analysis.The MEDLINE search yielded172articles,and the EMBASE search yielded70 articles;91met our inclusion criteria.The articles excluded consist of review/editorial articles(n=24)and articles608H.H.Tan et al.describing forensic reports (n =11),laboratory (n =8),and epidemiologic (n =4)studies where there is insufficient clinical data (eg,some forensic reports only stated that the patient was found dead).Articles that described only the therapeutic use of the AAPM and the adverse effects that occurred during therapeutic use were also excluded (n =40).The remainder of the articles were repeat articles (n =29)or did not involve the atypical antipsychotics listed (n =33).One case was reported twice in the literature [4,5];the findings of these cases were only included once.One foreign language report could not be located [6].Other searches identified 57additional reports.The review of meeting abstracts found 37reports,the AAPCC annual report identified 8cases,and our manual bibliography identified 12additional reports,of which,one is an abstract.3.2.Pediatric patientsWe identified 13pediatric (age,b 7years)patients that had case level data reported [7-17].The cases involved risperidone (n =3;dose range,1-4mg)[14,17],ziprasidone (n =1;400mg)[11],olanzapine (n =4;dose range,7.5-40mg)[7,12,13,15],and aripiprazole (n =5;dose range,2-195mg)[8-10,16].The details are reported in Table 1.Three olanzapine cases [7,12,15]and the ziprasidone case [11]developed sinus tachycardia (HR,N 160bpm).No reports described sinus tachycardia in this age group after ingestion of risperidone or aripiprazole.Two female patients had prolonged QTc intervals:a 17-month-old subject who ingested ziprasidone (400mg or 37mg/kg)[11]had a QTc interval of 480milliseconds and a 2.5-year-old subject who ingested aripiprazole (195mg or 17mg/kg)[8]had a QTc interval of 446milliseconds.There were no other apparent causes for QTc interval prolongation reported,and the resolution of the QTc interval was not documented.There were no cases with prolongation of the QRS interval,ventricular dysrhythmias,or hypotension.One patient who ingested 30to 40mg of olanzapine (approximately 3mg/kg)[7]was intubated.No patients required vasopressors,and all patients recovered fully.All but 1case series with summary data did not stratify patients younger than 7years from other pediatric patients.All pediatric case series are summarized in the next section.For the 7-to 16-year-old age group,we identified 22case level data reports [1,9,17-31].The details of the cases are shown in Table 1.Only 2patients had coingestants [26,27].Fifty-five percent (11/20)of the patients with single ingestion developed tachycardia,and 5had an HR of greaterTable 1Clinical effects described in case level reports for overdose of AAPMsRisperidoneOlanzapine Quetiapine Ziprasidone Aripiprazole Age,b 7n 3(2)4(4)NA 1(1)5(5)Dose1-4mg 7.5-40mg NA 400mg 11.9-195mg Tachycardia 03(3)NA 1(1)0Hypotension 00NA 00Incr QRS 00NA 00Incr QTc 00NA 1(1)1(1)V A 00NA 00Deaths 00NA 00Age,7-16n 6(5)5(4)7(7)NA 4(4)Dose21-110mg 100-275mg 600-3600mg NA 15-300mg Tachycardia 4(3)3(2)6(6)NA 0Hypotension 1(1)2(1)0NA 0Incr QRS 000NA 0Incr QTc 001(1)NA 0V A 000NA 0Deaths 001(1)NA0Age,N 16n 56(27)62(38)32(19)29(16)6(2)Dose9-270mg 50-1600mg 0.5-3.6g 0.24-12.8g 330-1260mg Tachycardia 22(10)35(25)17(11)3(0)2(0)Hypotension 13(4)7(3)12(8)2(0)2(0)Incr QRS 2(1)1(0)7(4)2(1)1(0)Incr QTc 10(5)2(1)11(5)13(6)2(0)V A 1(0)1(1)01(0)0Deaths4(0)5(2)1(1)2(0)1(0)Numbers in parenthesis are the number of cases where the AAPM was the only exposure.NA indicates no reports available;Incr QRS,increased QRS interval;Incr QTc,increased corrected QT interval;V A,ventricular arrhythmia.609Cardiovascular effects after AAPM overdosethan140bpm[1,18,22,30,32].The smallest single ingestions associated with tachycardia of greater than140bpm was275 mg for olanzapine[18]and600mg for quetiapine[32].The only patient with a significantly prolonged QTc interval was a14-year-old boy who ingested his own quetiapine(26mg/ kg)[19].His QTc interval was500milliseconds1hour after ingestion,and it returned to normal within8hours.He also had a tachycardia of128/min.His mental state was normal. No patients had prolongation of the QRS interval.Three patients(2olanzapine[18,27]and1risperidone[28]) developed hypotension;one of the patients who ingested olanzapine[27]was treated with vasopressors.There were no ventricular dysrhythmias,and2patients who ingested olanzapine required intubation[27,31].The only reported death occurred after the ingestion of2 quetiapine tablets of unknown strength[1].On initial evaluation,the patient was apparently well except for a tachycardia of150/min;she was transferred to the psychiatric ward,and6hours later,she was found seizing with fixed and dilated pupils.The electrocardiographic rhythm and intervals were not reported.There was no discussion of a possible coingestionFive case series data without patient level information were identified for patients younger than19years(Table2) [33-37].The cases described in the case series have similar findings to the case report data.One case series reported 1036risperidone exposures[35];there were3case series reporting485aripiprazole exposures[33,34,37]and1report detailing7ziprasidone exposures[36].There were no deaths, ventricular dysrhythmias,or cases of prolonged QTc interval reported.The most common cardiovascular abnormality was tachycardia,which occurred in3%[35]to19%[37]of patients in the reports.There was no report of any cases requiring intubation.One case series reported a0.5%(2/401) rate of hypotension[34].There were no case series reporting only summary data for quetiapine or olanzapine ingestions.3.3.Adult patientsWe identified102reports[4,11,17,18,24,30,31,38-123, 124-129]describing185patients with case level data (including cases with undefined age)[105].One hundred eighty-two patients ingested a single AAPMs,and3 patients ingested2AAPMs[11,56,109].A summary of the identified adult cases is shown in Table1.Forty-five percent of patients had coingestants,and78%involved acute ingestion of the patient's own medication.Reports were generally equally distributed between male and female subjects for each medication.Among patients with single-substance ingestion,tachy-cardia occurred in most quetiapine and olanzapine ingestions (N50%)and was common after risperidone ingestion(37%) but was not reported after ziprasidone or aripiprazole ingestion.Tachycardia usually occurred within8hours of ingestion and rarely lasted more than48hours.Prolonged QTc interval was reported in38cases(63% were female subjects).Two of these cases involved ingestion of2AAPM(one ingested quetiapine and ziprasidone[11], and the other ingested risperidone and ziprasidone[109]). There was only1patient with a prolonged QTc interval who developed a dysrhythmia.A30-year-old female patient ingested an unknown amount of ziprasidone and developed TdP8hours after the exposure.This patient coingestedTable2Summary of clinical effects after overdose of AAPMs reported in case seriesRisperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Age,≤19No.of reports10013Patients1036NA NA7485 Tachycardia 3.0%NA NA14.3% 5.5%-18.8% Hypotension NR NA NA NR0.5% Incr QRS NR NA NA NR NR Incr QTc NR NA NA NR NR V A NR NA NA NR NR Deaths NR NA NA NR NRAge(any age range)No.of reports47634Patients16413348677622 Tachycardia12.5%-50%30.8%-70.3% 5.0%-77.8%30.8%-38.1% 4.4%-11.2% Hypotension NR 5.0%-16.2% 5.6%-28.6% 3.8%0.3%-2.1% Incr QRS NR NR 5.9%NR NR Incr QTc NR 3.8%-55%26.9%-38.9%9.5%NR V A NR NR NR NR NR Deaths NR NR NR NR NRNA indicates no reports available;NR,not reported in the manuscript;Incr QRS,increased QRS interval;Incr QTc,increased corrected QT interval;VA, ventricular arrhythmia.610H.H.Tan et al.amantadine,another medication associated with TdP [38].Two patients with prolonged QTc interval died —the first was the ziprasidone-amantadine case just described [38],and the other patient was a mixed overdose involving imipramine who died of sepsis and acute respiratory distress syndrome (ARDS)[17].There were 18cases where QTc interval was greater than 500milliseconds;however,there were other causes for QT prolongation in 10of these cases (4hypokalemia [4,66,97,101]and 6coingestions [38,58,62,109,124]).Of the 8cases with no other obvious cause for prolongation [11,67,81,84,92,129],the QTc interval ranged from 510to 684milliseconds.The lowest dose associated with QTc interval greater than 500milliseconds without another potential cause was 270mg for risperidone [92],2000mg for quetiapine [81],and 1040mg for ziprasidone [129].There were no reports of single-substance ingestion with QTc interval prolongation involving olanza-pine or aripiprazole.Approximately 7%(13/185)of patients had prolonged QRS interval.However,7of the patients had coingestants [31,58,65,70,80,120,123],and 6of these patients had coingested drugs that are known to prolong the QRS interval [31,58,65,70,120,123].Among patients without coingestants,the QRS interval duration ranged from 104to 286milliseconds [4,75,78,81,84,101]and was associated with tachycardia (n =2)[4,78]and hypotension (n =2)[4,78].The lowest dose producing QRS interval prolongation was 100mg of risperidone [101],2000mg of quetiapine [81],and 4020mg of ziprasidone [75].No deaths or ventricular dysrhythmias were reported in patients with prolonged QRS interval.Ventricular dysrhythmia occurred after overdoses of olanzapine [57],ziprasidone [38],and risperidone [125].The details are described in Table 3.The only single-substance ingestion to experience a ventricular dysrhythmia was a 62-year-old with no cardiac history who ingested 750mg of olanzapine [57].On admission,he was confused,with a blood pressure of 134/74,an HR of 125/min,and an oxygen saturation of 93%.In the intensive care unit,he developed nonsustained ventricular tachycardia,followed by cardiac asystole that lasted less than 2minutes before returning to sinus rhythm.He received immediate resuscita-tion,and the oxygen saturation never fell below 90%.He was intubated and remained obtunded until his death at day 57from congestive heart failure and pneumonia.There was no mention of prolonged QRS or QTc interval.Hypotension occurred in 15%(4/27)of risperidone [17,20,49],8%(3/38)of olanzapine [31,64,126],and 42%(8/19)of quetiapine [4,30,50,67,78,85,113]single-substanceTable 3Summary of case reports describing patients who had ventricular dysrhythmias or died after overdose of AAPMs MedicationBrief descriptionRisperidone 40/Female —coingested imipramine,benztropine,and ibuprofen and died of sepsis and ARDS.QTc was prolonged.Ventricular dysrhythmias were not documented.Risperidone 50/Male —coingested salicylate and lithium.Salicylate level was 133.5mg/dL.QTc and ventricular dysrhythmias were notdocumented.Risperidone 51/Female —coingested haloperidol and benztropine and was given multiple doses of activated charcoal with sorbitol.Developed paralytic ileus and ARDS.QTc and ventricular dysrhythmias were not documented.Risperidone 66/Male —coingested sertraline,clonidine,nifedipine,and clonazepam.Developed hyperthermia,recurrent seizure,andventricular fibrillation.QTc was not reported.Olanzapine 20/Female —coingested valproic acid and acetaminophen.Valproic acid level was 2059m g/mL.QTc and ventriculardysrhythmias were not documented.Olanzapine 38/Male —autopsy result:intracranial hemorrhage.QTc and ventricular dysrhythmias were not documented.Olanzapine 62/Male —coingested phenelzine,had initial ventricular tachycardia and asystole,and died 57d later from pneumonia andheart failure.Olanzapine “Young ”/female –phenelzine contributed to death;had refractory seizure and hypotension.QTc and ventricular dysrhythmiaswere not documented.Olanzapine 24/Male —coingested alprazolam;found in asystolic arrest of unknown time with possible aspiration;successfulresuscitation but collapsed again.QTc and ventricular dysrhythmias were not documented.Quetiapine 15/Female —with initial HR of 150bpm;found seizing and had fixed dilated pupils in psychiatric ward 6h later.QTc andventricular dysrhythmias were not documented.Quetiapine 52/Male —found comatose with acute respiratory distress;failed resuscitation.Autopsy result was cardiomegaly withbilateral pulmonary congestion.QTc and ventricular dysrhythmias were not documented.Ziprasidone 37/Female —coingested acetaminophen,diphenhydramine,and clonazepam.Autopsy:centrilobular necrosis;acetaminophen level:899μg/mL;cause of death probably from acetaminophen.QTc and ventricular dysrhythmias were not documented.Ziprasidone 30/Female —coingested amantadine and ibuprofen;developed TdP 8h after presentation and then died 10d later from effectsof cardiac arrest;had hypokalemia and bradycardia at presentation.QTc was prolonged and patient had ventricular dysrhythmias.Aripiprazole 24/Male —coingested sertraline,trazodone,methamphetamine,and lithium.Probable cause of death:drug-inducedhyperthermia.QTc and ventricular dysrhythmias were not documented.611Cardiovascular effects after AAPM overdosecases.There were no patients with single-substance ingestion of ziprasidone or aripiprazole who had hypotension reported. Only28%(10/36)of hypotensive patients required ino-tropes,and the only single-substance overdose requiring vasopressors was a patient who ingested a large(560mg) amount of olanzapine[64].There were13adult deaths reported(Table3).After review,the deaths were attributable(at least partly)to the coingestion for10of the cases.In these cases,the AAPM were risperidone(n=4)[1,17,125,127],olanzapine(n=3) [105,112,128],ziprasidone(n=2)[1,38],and aripiprazole (n=1)[1].The coingestants included imipramine,halo-peridol,benztropine,nifedipine,sertraline,clonidine,clona-zepam,acetaminophen,valproic acid,salicylate,trazodone, alprazolam,phenelzine,amantadine,ibuprofen,diphenhy-dramine,methamphetamine,and lithium.Three of the deaths involved single-substance AAPM ingestion.One case was the patient who ingested750mg of olanzapine previously described[57].The second patient had a history of cardiac arrhythmia and hypertension and was found comatose and in respiratory distress after the ingestion of quetiapine[72]. There was no rhythm reported,and autopsy revealed cardiomegaly and bilateral pulmonary congestion.Both of these patients had measurable drug levels to confirm exposure.The final death involved a single-substance exposure to olanzapine,but the autopsy revealed intracranial hemorrhage[126].We identified24case series(involving all age ranges)that reported1482overdose patients[33,64,67,113,124,129-146,154].The findings of these reports are summarized in Table2.The most common abnormality was tachycardia. QTC interval prolongation was only reported in6of the case series(3quetiapine[67,130,138],2olanzapine[64,146],and 1ziprasidone[129]).QTc interval prolongation seems to be common after quetiapine and olanzapine ingestion.QRS interval prolongation was only reported after ingestion of quetiapine.The rate of patients developing hypotension varied from0.3%for aripiprazole[140]and up to29%for quetiapine[130].There were no reported deaths or ventricular dysrhythmias in any case series.4.DiscussionAcute overdose of risperidone,olanzapine,quetiapine, and ziprasidone have been reported to cause mild to moderate cardiovascular toxicity in some cases.There are few case level data describing aripiprazole ingestion,but the large number of patients reported in case series suggest that cardiovascular toxicity is minimal.No serious cardiovascular effects were noted in children younger than7years for any of these medications.We found some reports of serious cardiovascular toxicity among adolescent and adult patients who deliberately ingested AAPM,but these were primarily hypotension.There were no clinically significant dysrhyth-mias clearly attributable to AAPM toxicity.Although our methodology does not allow us to make precise estimates of the incidence of these events,we believe that the absence of published reports suggests that they are very rare.Cardiovascular toxicity is frequently the life-threatening event after poisoning.Psychiatric medications such as tricyclic antidepressants and older APMs(such as chlorpro-mazine)produce arrhythmias and profound hypotension in overdose.Other typical APMs(such as haloperidol)are less likely to have profound cardiovascular toxicity;however, these drugs alter cardiac repolarization and have been associated with TdP[147-150].Thus,APMs have a long history of cardiotoxicity after overdose,and this legacy has led many to assume that overdose of the AAPM will also produce significant cardiovascular toxicity.Cardiovascular toxicity can present with alterations in blood pressure(most often hypotension)or changes in intracardiac conduction such as prolongation of the QRS interval or QT intervals,or ventricular dysrhythmias.Hypoten-sion may be due to vasodilation,impaired myocardial contractility,or both.Chlorpromazine and tricyclic antide-pressants are both thought to cause vasodilatation by blocking peripheralα-adrenergic receptors[151].The AAPMs studied have a high affinity ofα1-adrenergic receptors[152], suggesting that they may also cause vasodilation and hypotension.However,in our review,hypotension was an uncommon finding for all medications except quetiapine.In addition,only28%of hypotensive patients required treatment with vasopressors,suggesting that the hypotension was not life threatening or responded to fluid infusion.Cardiac dysrhythmias may be caused by several mechan-isms.The2most commonly suggested for psychiatric medications are sodium channel antagonism(producing prolonged QRS interval duration and ventricular dysrhyth-mias)and potassium channel antagonism(producing QTc interval prolongation and TdP).We found reports of QRS interval prolongation after acute single-substance ingestion overdose of risperidone,quetiapine,and ziprasidone.In vitro studies suggest that risperidone,olanzapine,and ziprasidone have relatively low affinity for cardiac sodium channels,and our findings confirm that QRS interval prolongation is not a common effect for these drugs[153].The affinity of quetiapine for cardiac sodium channels is not well described, but a number of quetiapine overdose reports describe QRS interval prolongation similar to the type1A antidysrhyth-mics.However,we did not identify any cases of cardiovas-cular collapse,suggesting that quetiapine overdose is better tolerated than overdose of other drugs that prolong the QRS interval(eg,tricyclic antidepressants).There was1case of ventricular tachycardia that was documented after a large olanzapine overdose[57].As previously noted,olanzapine has a very low affinity for cardiac sodium channels[153], and the case did not report QRS interval widening(an effect that would indicate sodium channel antagonism)before the dysrhythmia.Given the patient's age,it is possible that this dysrhythmia was due to ischemia rather than drug effect.612H.H.Tan et al.Prolongation of the QTc interval has been reported with therapeutic use of many antipsychotic medications.Studies have suggested a link between these medications and sudden death,leading to a hypothesis that medication-induced prolongation of the QTc interval may produce dysrhythmias. These studies have focused on chronic use;however,the conclusions have been generalized to overdose patients. Although we found that QTc interval prolongation was frequently reported after overdose,we identified only1case where TdP was documented.This case was ziprasidone ingestion with an unknown dose;the patient also ingested amantadine,another medication that has been associated with TdP[38].No case series data reported TdP.Not surprisingly,there were several deaths occurring after overdose of these medications.Many of these cases involved multiple agents,and in several,we felt that the death was likely due to a nonpoisoning cause or a coingestion.In2 cases,there was not another clear cause—one patient was found in respiratory arrest[72],and a second patient had a seizure and was found dead in a psychiatric ward[1].It is possible that either of these patients had a dysrhythmia that was missed.There is no evidence to suggest dysrhythmia as the main cause of death.There were no ventricular dysrhythmias reported among the case series data.5.LimitationsOur study is a review of the literature,and therefore,our conclusions are limited by the available cases and reported information.We found very few reports of aripiprazole poisoning.It is possible that future reports will differ significantly from the currently available information.Our search did not include clozapine or paliperidone.It is possible that these APMs may systematically differ from the ones included.However,paliperidone is the active metabo-lite of risperidone,so it is likely that the effects in overdose will be similar.It is certainly possible that dysrhythmias after overdoses of these medications have occurred but not been reported.However,it seems likely that reporting bias would favor the publication of cases with life-threatening effect rather than underestimate the severity of cases.This is further supported by the case series data that suggest that severe cardiovascular toxicity is rare after overdose of AAPM. 6.ConclusionsOur review suggests that the most common cardiovas-cular effects that occur after AAPM overdose are tachycar-dia,mild hypotension,and prolongation of the QT interval. Prolongation of the QRS interval was very uncommon after ziprasidone and risperidone single ingestion,but there were multiple cases after quetiapine ingestions.We found no reports where ventricular dysrhythmias(including TdP) could be clearly attributed to AAPM overdose. AcknowledgmentsThe authors thank Emily Robbins for her assistance in locating articles.References[1]Lai MW,Klein-Schwartz W,Rogers GC,et al.2005Annual Reportof the American Association of Poison Control Centers'National Poisoning and Exposure Database.Clin Toxicol2006;44:803-932.[2]Burns MJ.The pharmacology and toxicology of atypical antipsy-chotic agents.J Toxicol Clin Toxicol2001;39(1):1-14.[3]Priori SG,Schwartz PJ,Napolitano C,et al.Risk stratification in thelong-QT syndrome.N Engl J Med2003;348(19):1866-74.[4]Gajwani P,Pozuelo L,Tesar GE.QT interval prolongation associatedwith quetiapine(Seroquel)overdose.Psychosomatics2000;41(1): 63-5.[5]Hustey FM.Acute quetiapine poisoning.J Emerg Med1999;17(6):995-7.[6]Berecz R,Kellermann M,Glaub T,Degrell I.Olanzapine intoxica-tion.A case report.Psychiatr Hung2000;15:176-8.[7]Catalano G,Cooper DS,Catalano MC,Butera AS.Olanzapineoverdose in an18-month-old child.J Child Adolesc Psychopharma-col1999;9(4):267-71.[8]Seifert SA,Schwartz MD,Thomas JD.Aripiprazole(abilify)overdose in a child.Clin Toxicol(Phila)2005;43(3):193-5.[9]Lofton AL,Klein-Schwartz W.Atypical experience:a case series ofpediatric aripiprazole exposures.Clin Toxicol(Phila)2005;43(3): 151-3.[10]Schonberger RB,Douglas L,Baum CR.Severe extrapyramidalsymptoms in a3-year-old boy after accidental ingestion of the new antipsychotic drug aripiprazole.Pediatrics2004;114(6):1743. [11]Bryant SM,Zilberstein J,Cumpston KL,Magdziarz DD,CosterisanDD.A case series of ziprasidone overdoses.Vet Hum Toxicol2003;45(2):81-2.[12]Bonin MM,Burkhart KK.Olanzapine overdose in a1-year-old male.Pediatr Emerg Care1999;15(4):266-7.[13]Bond GR,Thompson JD.Olanzapine pediatric overdose.Ann EmergMed1999;34(2):292-3.[14]Cheslik TA,Erramouspe J.Extrapyramidal symptoms followingaccidental ingestion of risperidone in a child.Ann Pharmacother 1996;30(4):360-3.[15]Yip L,Dart RC,Graham K.Olanzapine toxicity in a toddler.Pediatrics1998;102(6):1494.[16]Roche K,Clark R,Sangalli B,McKay CA,Bayer MJ.Aripiprazoleingestion in two pediatric patients.Clin Toxicol2004(42):738-9. [17]Acri AA,Henretig FM.Effects of risperidone in overdose.Am JEmerg Med1998;16(5):498-501.[18]Theisen FM,Grabarkiewicz J,Fegbeutel C,Hubner A,Mehler-Wex C,Remschmidt H.Olanzapine overdose in children and adolescents:two case reports and a review of the literature.J Child Adolesc Psychopharmacol2005;15(6):986-95.[19]Kurth J,Maguire G.Pediatric case report of quetiapine overdose andQTc prolongation.Ann Clin Psychiatry2004;16(4):229-31. [20]Magdalan J,Wasyko-Smolarek M,Antonczyk A,Kochman K,Przewlocki M,Porebska B.Intoxications with atypical antipsychotic drugs—data of the Acute Intoxication Unit in Wroclaw.Przegl Lek 2004;61(4):392-6.613Cardiovascular effects after AAPM overdose。