a b s t r a c t

Background: Antipsychotic/Antidepressant use is a risk factor for QT interval (QT) prolongation and sudden car- diac death. However, it is unclear which drugs are risk factors for QT prolongation and Torsades de Pointes in cases of psychotropic drug overdose.

Methods: After correction of QT data by Bazett formula (QTc), QTc was classified into 3 categories (QTc b 440 mil- liseconds, 440 milliseconds <= QTc b 500 milliseconds, and QTc >= 500 milliseconds), and the Blood concentration of each drug was classified as not detected, therapeutic range, or toxic range. The association of the blood concen- tration of each drug with QTc was analyzed using the ordinal logistic regression model. Drugs that induced QT- heart rate pairs higher than the at-risk line of Isbister’s QT-heart rate nomogram (QT nomogram) were further analyzed using the binomial logistic regression model.

Results: A total of 649 patients were enrolled in the study. The independent risk factors for QTc prolongation were therapeutic and toxic range of phenotiazine antipsychotic drug (therapeutic range: odds ratio [OR], 1.56 [P = .039]; toxic range: OR, 3.85 [P b .001]), and toxic range of cyclic antidepressants (OR, 2.39; P = .018). In addition, toxic range of phenotiazine antipsychotic drug (OR, 3.87; P = .012) and tricyclic antidepressants (OR, 4.94; P b .001) were risk factors for QT higher than the at-risk line of the QT nomogram.

Conclusions: The possibility of QT prolongation and torsades de pointes due to overdose of phenotiazine antipsy- chotic drug or tricyclic antidepressants requires particular consideration.

(C) 2014

Introduction

Torsades de pointes (TdP) is defined as Polymorphic ventricular tachycardia and is a Lethal arrhythmia that may shift to ventricular fi- brillation. QT interval (QT) prolongation on an electrocardiogram is a risk factor for the development of TdP. QT interval prolongation is in- duced most frequently by congenital QT prolongation syndrome and next most frequently by drugs [1]. Drug-induced QT prolongations can be caused by drugs that block the rapid delayed rectifier potassium cur- rent (IKr), which is mediated by the human ether-a-go-go related gene (hERG) [2].

QT prolongation is a clear risk factor for TdP and sudden cardiac death [3]. However, no established criteria are available at present re- garding the level of QT prolongation that leads to TdP and sudden cardi- ac death [4]. For the evaluation of QT prolongation, corrected QT (QTc) using Bazett formula has been widely used to adjust for the influence of heart rate [5]. Although the reference range of Bazett QTc is consid- ered to be less than 440 milliseconds, significant individual differences have been seen. The risk of TdP has been reported to increase when

* Corresponding author. Tel.: +81 463931121; fax: +81 463933751.

E-mail address: [email protected] (N. Miura).

QTc is greater than 500 milliseconds [4]. In addition, in recent years, QT-heart rate nomogram analysis methods introduced by Isbister (QT nomograms) have been used for TdP risk evaluation [6,7].A system- atic review of cases of drug-induced TdP demonstrates that a QT-heart rate pair higher than the at-risk line on the QT nomogram is a risk factor for the onset of TdP, and this measurement predicts onset with greater accuracy than the use of a QTc of 440 or 500 milliseconds as a criterion [6]. therapeutic use of an antipsychotic/antidepressant is a risk factor for QT prolongation [8-15], sudden cardiac death, and lethal arrhythmia [16-22]. QT prolongation is also thought to be a risk factor for adverse cardiovascular events in patients with Drug overdoses, including cases of antipsychotic and antidepressant overdose [23]. Overdose of some antipsychotics/antidepressants has also been reported to cause QT pro- longation and TdP [24-27]. However, no sufficient studies have been conducted on the drugs for which overdose is a risk factor for QT prolon- gation and TdP in cases of psychotropic drug overdose in the emergency

department (ED) [14].

Both dose estimation and risk assessment of TdP must be performed using methods as trustful as possible for clarifying the risk of TdP in psy- chotropic drug overdose. Therefore, in the present study, we investigat- ed the relationships between blood concentrations of psychotropic drugs and risk of QT prolongation and TdP by using QTc and QT nomo- grams in patients with psychotropic drug overdose who visited our ED.

http://dx.doi.org/10.1016/j.ajem.2014.09.048

0735-6757/(C) 2014

Materials and methods

Study design and setting

This retrospective study enrolled consecutive adult ED patients with acute psychotropic drug overdose between April 2009 and March 2012. The ED at Tokai University Hospital was used for enrollment. The annual visit volume for the Tokai University ED is in excess of 20000 patients and it is staffed 24 hours per day with board-certified emergency physi- cians. A 12-lead electrocardiogram was performed after arrival at the ED.

Study population

Clinical records were collected for adult patients who were diag- nosed as having acute psychotropic drug overdose by oral ingestion. After eligibility screening, we applied inclusion and exclusion criteria to determine whether patients were analyzed. Inclusion criteria were as follows: age >=18 years, acute presentation (presentation within 24 hours of exposure), a detected psychotropic drug in the blood sample, and clinically suspected poisoning. Exclusion criteria were as follows: alternative diagnosis (per the primary clinical team, eg, trauma, drown- ing, or infection), chronic presentation (ie, not acute), the presence of opioids, methamphetamine, amphetamine, over-the-counter drugs, or other drugs (cardiovascular drugs, H1 receptor inhibitors, muscle relax- ants, theophylline), as well as nondrug (eg, plants and Chemical agents) overdoses and subjects with incomplete data.

Of 997 patients screened, we excluded 348 patients because of miss- ing ECG data, combination poisoning with other drugs or substances, and Alternative diagnoses. Thus, 649 patients were analyzed. The enroll- ment algorithm with inclusion and exclusion criteria is illustrated in Figure.

Data collection

Using a standardized data collection instrument, we collected in- formation on age, sex, psychiatric disorders, cardiovascular disease (including arrhythmia and ischemic or valvular heart disease), expo- sure information (drug name, drug group, serum drug concentra- tions), vital signs, Serum potassium concentration (in mEq/L, drawn at the bedside during the ED), serum alcohol concentration (in mg/dL, drawn at the bedside during the ED), adverse clinical find- ings (confusion as indicated by Glasgow Coma Scale score <= 8, tachycardia as indicated by heart rate >= 100 beats/min, hypotension as indicated by systolic blood pressure <= 90 mm Hg, convulsion, ven- tricular tachycardia, TdP), admission status, and in-hospital death. Histories were extracted from the medical records based on patient or family self-reports.

Electrocardiogram measurements

All 12-lead ECGs were performed during the initial ED visit using a standard paper speed of 25 mm/s with standard lead positions. QT in- terval was measured in each lead of the ECG using a clear ruler or by counting the grid squares on the ECG paper when the paper rate was 25 mm/s. The QT was measured from the beginning of the Q wave until the T wave returned to the baseline (isoelectric line). The QT was measured through a total of 6 leads, including 3 limb leads (I, II, and aVF) and 3 chest leads (V2, V4, and V6), and the median of the 6 individ- ual leads was calculated. The heart rate was obtained from the automat- ed readout of the ECG machine and was an average measure of the RR interval for the 12-lead ECG. Only the absolute QT was used. Corrected QT was derived using Bazett formula (QT/RR^1/2). The QT was plotted against the heart rate on the QT nomogram using the methods of Isbister [28].

*Cardiovascular drug, H1 receptor inhibitor, Muscle relaxant, theophylline

87 excluded

(trauma, drowning, or infection)

Adult patients with suspected acute poisoning and a psychotropic drug detected in the blood arrived at the ED between April 2009 and March 2012

(n = 997)

125 excluded

• 53 OTC drug overdose
• 34 pesticide, chemical

poisoning

• 25 other drug* overdose
• 13 carbon monoxide poisoning

Adult patients with acute poisoning (n = 910)

Enrolled patients with

acute psychotropic drug overdose (n = 649)

136 excluded (missing ECG data)

acute psychotropic drug overdose (n=785)

Figure. Study flowchart.

drug exposure“>Drug classification

The blood sample that was drawn at the bedside during the ED visit for acute drug overdose was analyzed for its serum drug concentrations using gas chromatography mass spectrometry and/or liquid chromatog- raphy tandem mass spectrometry. Serum drug concentrations were classified as not detected (undetectable), within the therapeutic range (treatment level), or within the toxic range (greater than the treatment level) [29]. Detected drugs were classified into the following groups: phenotiazine antipsychotic drugs (levomepromazine, chlorpromazine, promethazine, propericiazine, perphenazine), butyrophenone antipsy- chotic drugs (haloperidol), aTypical antipsychotic drugs (quetiapine, risperidone, olanzapine, perospirone), benzamide antipsychotic drugs (sulpiride), cyclic antidepressants (tricyclic antidepressants amitriptyline, nortriptyline, clomipramine, desipramine, imipramine, and amoxapine; tetracyclic antidepressants maprotiline and mianserin), selective seroto- nin reuptake inhibitors (SSRIs; paroxetine, fluvoxamine, sertraline), other antidepressants (serotonin and norepinephrine reuptake inhibitor [SNRI] milnacipran, and noradrenergic and specific serotonergic antide- pressants [NaSSAs] mirtazapine and trazodone), lithium, barbiturates (phenobarbital and pentobarbital), sodium valproate, carbamazepine, benzodiazepines, and nonbenzodiazepine hypnotics (zopiclone and zolpidem). Multidrug exposures were defined as exposure to more than 1 drug group and did not include exposure to 2 drugs of the same drug group (eg, exposure to amitriptyline and nortriptyline counted as 2 drug exposures, but only 1 drug group). When more than 2 drugs belong- ing to the same drug group were detected, we performed serum drug level classifications based on the drug with the highest concentration.

Analysis

Corrected QT were classified into 3 ordinal groups, as follows: 0, QT b 440 milliseconds; 1, 440 milliseconds <= QT b 500 milliseconds; and 2, QT

>= 500 milliseconds. Furthermore, QTc groups were defined ordinal out- come variables and were analyzed with the use of an ordinal logistic regression model. Analyzed predictor variables were as follows: age, sex, psychiatric disorder, serum potassium concentration, serum alcohol concentration, heart rate, and the presence of phenotiazine antipsychotic drugs, atypical antipsychotic drugs, benzamide antipsychotic drugs, cyclic antidepressants, SSRIs, other antidepressants, lithium, sodium valproate, carbamazepine, benzodiazepines, and nonbenzodiazepine hypnotics. Cases of butyrophenone antipsychotic drug overdose were rare (butyrophenone antipsychotic drugs were detected in blood sam- ples from only 2 patients); therefore, we did not assess overdoses of butyrophenone antipsychotic drugs.

QT-heart rate pair values were classified into values higher than or lower than the at-risk line of the QT nomogram. A QT-heart rate pair higher than the QT nomogram at-risk line was defined as the outcome variable, and the odds ratio (OR) and 95% confidence interval (CI) for overdose of each psychotropic drug (phenotiazine antipsychotic drugs, atypical antipsychotic drugs, benzamide antipsychotic drugs, tricyclic antidepressants, SSRIs, other antidepressants, lithium, sodium valproate, benzodiazepines, and nonbenzodiazepine hypnotics) were calculated using the binominal logistic regression model. In addition, we calculated ORs and 95% CIs for the psychotropic drugs using the adjusted binominal logistic regression model. Adjusted covariates were age, sex, and serum potassium concentration. A P value of less than .05 was considered statis- tically significant. No case of a QT-heart rate pair higher than the QT nomo- gram at-risk line was identified for overdose of tetracyclic antidepressants and carbamazepine; therefore, we did not analyze these drugs.

Statistical analysis

Statistical analysis was performed with SPSS software version 20 (IBM Corp, Armonk, NY). The Mann-Whitney U test and the Kruskal- Wallis test were used to analyze continuous and ordinal variables. The

?² test (with Fisher exact test when appropriate) was used to analyze categorical variables.

Results

Participants

Patients had a median age of 37 years (interquartile range [IQR], 28-45 years), and there were 496 women (76.4%). The ED admittance status for the 649 subjects was as follows: 468 (72.1%) admitted and 181 (27.9%) discharged. Major adverse clinical findings were confusion (25.4%), tachycardia (22.1%), hypotension (10.3%), convulsion (0.4%), and ventricular tachycardia (0.1%), but TdP and in-hospital death did not occur. Corrected QT prolongation (QTc >= 440 milliseconds) occurred in 40.5% of patients. Severe QTc prolongation (QTc >= 500 milliseconds) occurred in only 20 patients (3.0%). QT-heart rate pairs higher than the nomogram at-risk line were observed in 35 patients (5.4%). All baseline characteristics are summarized in Table 1.

Drug exposure

The top 5 most common drug groups in the present study, in de- scending order, were benzodiazepines (n = 567), phenotiazine anti- psychotic drugs (n = 175), SSRIs (n = 162), atypical antipsychotic drugs (n = 145), and nonbenzodiazepine hypnotics (n = 100). Multi- drug exposures were recorded for 482 patients, and single-drug expo- sures were primarily benzodiazepine overdoses. Each number of classified serum drug concentration is summarized in Table A.1.

Main analysis

The demographic characteristics of QTc groups and QT-nomogram groups are summarized in Table 2. Groups with QTc prolongation were older, tended to be female, and had lower serum potassium con- centrations, lower levels of consciousness, and faster heart rates. Groups with QT-heart rate pairs higher than the QT nomogram at-risk line tended to have faster heart rates.

The analyses of QTc prolongation with the ordinal logistic regression model are summarized in Table 3. Age, female sex, serum potassium, and heart rate were independent risk factors. In addition, concentra- tions of phenotiazine antipsychotics in the therapeutic and toxic ranges were independent risk factors for QTc prolongation (therapeutic range: OR, 1.56 [95% CI, 1.02-2.39; P = .039]; toxic range: OR, 3.85 [95% CI,

1.85-8.02; P b .001]). The presence of a cyclic antidepressant in the

Table 1

Characteristics of the study population

Age (y), median (IQR) 37 (28-45)

Age N 50 y, no. (%) 94 (14.4)

Sex, female, no. (%) 496 (76.4)

Psychiatric disorder, no. (%) 587 (90.4)

Cardiovascular disease, no. (%) 12 (1.8)

Level of consciousness (GCS) 14 (9-15)

Confusion (GCS 3/4 8), no. (%) 165 (25.4)

Systolic blood pressure (mm Hg) 112 (100-128)

Hypotension (SBP 3/4 90 mm Hg) 67 (10.3)

Heart rate (beats/min) 84 (71-99)

Tachycardia ( 3/4 100 beats/min) 144 (22.1)

Convulsion, no. (%) 3 (0.4)

Ventricular tachycardia, no. (%) 1 (0.1)

TdP, no. (%) 0 (0)

Serum potassium (mEq/L) 3.7 (3.5-4.0)

QTc 3/4 440 milliseconds, no. (%)	263 (40.5)
QTc 3/4 500 milliseconds, no. (%)	20 (3.0)
QT nomogram, no. (%) (higher than at-risk line of QT nomogram)	35 (5.4)
Admission, no. (%)	468 (72.1)
Length of stay (d), median (IQR)	2 (0-4)
Death, no. (%)	0 (0)

Table 2

Demographic characteristics by QTc interval and QT nomogram

Variable		QTc interval			QT nomogram
	440 N QTc (n = 386)	440 <= QTc b 500 (n = 243)	QTc >= 500 (n = 20)		Low (n = 614)	High (n = 35)
Age (y), median (IQR)	36 (27-44)	37 (30-46)	45 (35-54)		36 (28-45)	38 (31-46)
Age N 50 y	54	36	4		90	4
Sex (female)	280	197	19		466	30
Psychiatric disorder	350	223	14		560	27
Cardiovascular disease	8	3	1		11	1
GCS, median (IQR)	14 (10-15)	13 (7-15)	11.5 (8-14)		14 (9-15)	11 (6-14)
Systolic blood pressure (mm Hg), median (IQR)	113 (100-125.75)	110 (100-130)	112.5 (104.5-121)		112 (100-128)	115 (100-121)
Heart rate (beats/min), median (IQR)	73.5 (62-88)	84 (73-95)	98 (78-100)		78 (66-91)	99 (60-113)
Serum potassium (mEq/L), median (IQR)	3.8 (3.5-4)	3.7 (3.4-4)	3.6 (3.3-3.8)		3.7 (3.5-4)	3.6 (3.4-3.9)
Alcohol
<=100	363	220	16		569	30
N 100, <=200	15	13	3		27	4
N 200	8	10	1		18	1
Phenotiazine antipsychotic drugs
n.d.	305	155	14	454		20
Therapeutic range	72	65	3	130		10
Toxic range	9	23	3	30		5
Atypical antipsychotic drugs
n.d.	301	184	19	476		28
Therapeutic range	20	12	0	31		1
Toxic range	65	47	1	107		6
Benzamide antipsychotic drugs
n.d.	354	216	19	557		32
Therapeutic range	21	13	1	33		2
Toxic range	11	14	0	24		1
Cyclic antidepressants
n.d.	344	208	16	539		29
Therapeutic range	29	15	1	45		0
Toxic range	13	20	3	30		6
Tricyclic antidepressants
n.d.	351	210	16	548		29
Therapeutic range	24	16	1	41		0
Toxic range	11	17	3	25		6
SSRIs
n.d.	292	178	17	459		28
Therapeutic range	64	45	1	108		2
Toxic range	30	20	2	47		5
Other antidepressants
n.d.	324	188	19	500		31
Therapeutic range	43	27	1	69		2
Toxic range	19	28	0	45		2
Lithium
n.d.	374	233	19	593		33
Therapeutic range	7	3	1	10		1
Toxic range	5	7	0	11		1
Sodium valproate
n.d.	352	205	18	542		33
Therapeutic range	27	25	2	52		2
Toxic range	7	13	0	20		0
Carbamazepine
n.d.	376	236	20	597		35
Therapeutic range	4	4	0	8		0
Toxic range	6	3	0	9		0
Benzodiazepines
n.d.	40	39	3	78		4
Therapeutic range	58	29	1	85		3
Toxic range	288	175	16	451		28
Nonbenzodiazepine hypnotics
n.d.	300	202	16	490		28
Therapeutic range	26	7	1	32		2
Toxic range	60	34	3	92		5

n.d., not detected.

toxic range was also an independent risk factor for QTc prolongation (OR, 2.39 [95% CI, 1.16-4.91; P = .018]). Toxic concentrations of atypical antipsychotic drugs, benzamide antipsychotic drugs, SSRIs, other anti- depressants, lithium, carbamazepine, sodium valproate, and benzodiaz- epines were not independent risk factors for QTc prolongation. The presence of nonbenzodiazepine hypnotics in their therapeutic ranges was an independent risk factor for QTc shortening (OR, 0.35 [95% CI, 0.15-0.85; P = .021]).

Unadjusted and adjusted analyses of QT-heart rate pairs higher than the at-risk line of the QT nomogram are summarized in Table 4. After adjustment, phenotiazine antipsychotic drugs and tricyclic antidepressants in their toxic ranges were risk factors for QT-heart rate pair higher than the at-risk line of the QT nomogram (phenotiazine antipsychotic drugs: OR, 3.87 [95% CI, 1.35-11.1; P = .012]; tricyclic antidepressants: OR, 4.94 [95% CI, 1.83-13.3; P = .005]). Concentrations of atypical antipsychotic drugs, benzamide antipsychotic drugs, SSRIs, other antidepressants,

Table 3

Multivariate analysis, ordinal logistic regression model, Bazett QTc prolongation

	OR	95% CI	P
Age	1.02	1.00-1.03	.017
Sex, female	2.11	1.38-3.21	b.001
Psychiatric disorder	0.72	0.40-1.33	.295
Serum potassium (mEq/L) Alcohol, mg/dL <=100	0.70 Reference	0.50-0.97	.030
N 100, <=200	1.96	0.90-4.28	.090
N 200	2.01	0.77-5.29	.156
Heart rate (beats/min) 1.02		1.01-1.03	b.001

Phenotiazine antipsychotic drugs

n.d. Reference

Therapeutic range 1.56 1.02-2.39 .039

Toxic range 3.85 1.85-8.02 b.001 Atypical antipsychotic drugs

n.d.	Reference
Therapeutic range	0.80	0.36-1.77	.581
Toxic range	0.80	0.50-1.29	.362

Benzamide antipsychotic drugs

n.d.	Reference
Therapeutic range	1.38	0.65-2.94	.402
Toxic range	1.46	0.63-3.37	.373

Cyclic antidepressants

n.d	Reference
Therapeutic range	0.74	0.37-1.46	.386
Toxic range	2.39	1.16-4.91	.018

SSRIs

n.d.	Reference
Therapeutic range	0.98	0.62-1.55	.946
Toxic range	1.02	0.54-1.94	.940

Other antidepressants

n.d.	Reference
Therapeutic range	1.17	0.66-2.01	.580
Toxic range	1.90	0.93-3.90	.080

Lithium

n.d.	Reference
Therapeutic range	0.91	0.22-3.71	.896
Toxic range	0.96	0.24-3.79	.949

Sodium valproate

n.d.	Reference
Therapeutic range	1.48	0.80-2.73	.208
Toxic range	2.19	0.89-5.38	.087

Carbamazepine

n.d.	Reference
Therapeutic range	1.22	0.26-5.83	.805
Toxic range	0.65	0.15-2.85	.571

Benzodiazepines

n.d.	Reference
Therapeutic range	0.55	0.28-1.06	.073
Toxic range	0.66	0.40-1.08	.098
Nonbenzodiazepine hypnotics n.d.	Reference
Therapeutic range	0.35	0.15-0.85	.021
Toxic range	0.69	0.42-1.13	.141

lithium, sodium valproate, benzodiazepines, and nonbenzodiazepine hypnotics in their toxic ranges were not risk factors for QT-heart rate pair higher than the at-risk line of the QT nomogram.

Discussion

The results of the present study revealed that therapeutic or toxic blood concentrations of phenothiazine antipsychotic drugs and toxic blood concentrations of cyclic antidepressants upon admission to the ED are independent risk factors for QTc prolongation, even after adjusting for the influence of background factors and other drugs in pa- tients with drug overdoses. Toxic blood concentrations of atypical anti- psychotics benzamide antipsychotics (sulpiride), SSRIs, SNRIs, NaSSAs, trazodone, lithium, carbamazepine, Valproic acid, and benzodiazepines were not independent risk factors for QTc prolongation. A therapeutic concentration of nonbenzodiazepine hypnotics was an independent risk factor for QTc shortening. We observed 35 (5.4%) of 649 patients

Table 4

QT-nomogram, binominal logistic regression model

Variable^a Unadjusted OR (95% CI) Adjusted OR (95% CI) Age 1.01 (0.99-1.04)

Sex (female) 1.91 (0.73-5.00)

Psychiatric disorder 0.33 (0.14-0.75)

Serum potassium (mEq/L) 0.71 (0.37-1.37) Alcohol

<=100 Reference

N 100, <=200 2.81 (0.92-8.55)

N 200 1.05 (0.13-8.16)

Heart rate (beats/min) 1.02 (1.01-1.37)

Phenotiazine antipsychotic drugs

n.d. Reference Reference

Therapeutic range 1.75 (0.79-3.82) 1.89 (0.85-4.20)

Toxic range 3.78 (1.32-10.8) 3.87 (1.35-11.1)

Atypical antipsychotic drugs

n.d. Reference Reference

Therapeutic range 0.54 (0.07-4.16) 0.58 (0.76-4.44)

Toxic range 0.95 (0.38-2.36) 1.04 (0.41-2.63)

Benzamide antipsychotic drugs

n.d. Reference Reference

Therapeutic range 0.99 (0.23-4.31) 1.16 (0.26-5.12)

Toxic range 0.72 (0.95-5.51) 0.67 (0.09-5.20)

Tricyclic antidepressants

n.d. Therapeutic range	Reference N/A	Reference N/A
Toxic range	4.54 (1.73-11.9)	4.94 (1.83-13.3)

SSRIs
n.d.	Reference	Reference
Therapeutic range	0.30 (0.07-1.29)	0.32 (0.07-1.38)
Toxic range	1.74 (0.64-4.73)	1.87 (0.67-5.17)

Other antidepressants

n.d.	Reference	Reference
Therapeutic range	0.47 (0.11-2.00)	0.49 (0.12-2.11)
Toxic range	0.72 (0.17-3.10)	0.73 (0.17-3.18)

Lithium n.d.	Reference	Reference
Therapeutic range	1.80 (0.22-14.4)	2.13 (0.26-17.4)
Toxic range	1.63 (0.26-13.0)	1.70 (0.21-13.9)

Sodium valproate n.d.	Reference	Reference
Therapeutic range	0.63 (0.15-2.71)	0.69 (0.16-3.00)
Toxic range	N/A	N/A

Benzodiazepines n.d.	Reference	Reference
Therapeutic range	0.69 (0.15-3.17)	0.72 (0.16-3.36)
Toxic range	1.21 (0.41-3.55)	1.20 (0.41-3.54)

Nonbenzodiazepine hypnotics

n.d.	Reference	Reference
Therapeutic range	1.09 (0.25-4.80)	0.97 (0.22-4.32)
Toxic range	0.95 (0.36-2.53)	0.88 (0.33-2.35)

N/A, not applicable.

^a Confounding variables are age, sex, and serum potassium.

with QT-heart rate pairs that were higher than the at-risk line of the QT nomogram. Toxic blood concentrations of phenothiazine antipsy- chotics and tricyclic antidepressants were significant risk factors for QT-heart rate pairs higher than the at-risk line of the QT nomogram, even after adjusting for age, sex, and serum potassium concentration. These results suggest that it is necessary to consider the possibility of QT prolongation and TdP in cases where phenothiazine antipsychotic levomepromazine, chlorpromazine, promethazine, and/or tricyclic anti- depressant overdose is suspected in the ED.

A number of clinical studies have demonstrated that antipsychotics may cause QT prolongation by blocking the channel that mediates IKr [30,31], and therapeutic use of typical antipsychotics, in particular, in- duce QT prolongation [8,10,11]. In a study of neuropathic patients using antipsychotics, in which QT prolongation was defined as QTc >= 456 milliseconds, thioridazine was an independent risk factor [8]. In ad- dition, in a study of patients 18 years or older and prescribed psychotro- pics for schizophrenia, in which the upper normal limit of QTc was set at 453 milliseconds, flupenthixol decanoate, chlorpromazine, and flu- phenazine decanoate were risk factors for QT prolongation [11].

Atypical antipsychotics are thought to confer a lower risk of QT prolon- gation than that associated with typical antipsychotics [12]. In a study of patients prescribed psychotropics for schizophrenia, in which QT pro- longation in Males and females was defined as QTc N 450 and N 480 milliseconds, respectively, typical antipsychotics chlorpromazine and intravenous haloperidol, as well as the benzamide antipsychotic drug sultopride, were significant risk factors, whereas atypical antipsychotics such as olanzapine, quetiapine, risperidone, and zotepine were not [10]. In addition, according to a randomized intervention study that mea- sured QTc changes before and after drug administration, atypical anti- psychotics olanzapine, risperidone, and quetiapine were safer than typical antipsychotics, because they were less likely than thioridazine, and just as likely as oral haloperidol, to cause QTc prolongation [12]. This study also showed that ziprasidone is more likely to cause QTc pro- longation than olanzapine, risperidone, and quetiapine, and the risk of QT prolongation varies among atypical antipsychotics [12]. At the pres- ent time, it is unclear whether acute antipsychotic overdose causes QT prolongation owing to the scarcity of reports. It has been reported that in cases of thioridazine overdose, QTc is prolonged in an estimated dose-dependent manner and amisulpiride overdose is a risk factor for QT prolongation and TdP. However, it is unclear whether or not over- dose of other acute antipsychotics is the risk factor [24,25,27].

In a large number of clinical studies, patients taking antipsychotics

have shown a high risk of sudden death [16,21,32,33]. In a study inves- tigating the incidence of sudden cardiac death and lethal ventricular ar- rhythmia in users of antipsychotics, the adjusted Hazard ratios of such events were significantly higher when using chlorpromazine or halo- peridol, which are typical antipsychotics, in comparison to olanzapine, whereas the ratios were low when using quetiapine, an atypical anti- psychotics [18]. On the other hand, there is a report stating that patients currently using typical and atypical antipsychotics have a higher risk of sudden death than do patients using neither type of drug. In addition, the risk of sudden death increases in a dose-dependent manner [16]. The results above demonstrate that users of atypical antipsychotics are less likely to develop QT prolongation than users of typical antipsy- chotics, but do not necessarily have a lower risk of sudden death, indi- cating the involvement of various factors other than TdP in sudden death in users of antipsychotics [16].

In the present study, therapeutic or toxic blood concentrations of a typical phenothiazine antipsychotic drug were independent risk factors for QTc prolongation, whereas a toxic blood concentration of an atypical antipsychotic drug was not an independent risk factor in patients with psychotropic drug overdose. Similarly, a toxic blood concentration of a phenothiazine antipsychotic drug was also a risk factor for a QT-heart rate pair higher than the at-risk line of the QT nomogram, whereas a toxic blood concentration of an atypical antipsychotic drug was not. Therefore, it is speculated that phenothiazine antipsychotic overdose upon admittance to the ED carries a risk of TdP, whereas atypical anti- psychotic overdose has less risk.

Haloperidol, particularly when injected intravenously, is thought to be a risk factor for QT prolongation and TdP [34], but was excluded from the examined items in the present study, because butyrophenone antipsychotics were detected in only 2 patients and no patients showed toxic blood concentrations of these antipsychotics. In addition, no pa- tients in the present study were using thioridazine, a typical antipsy- chotic that is very likely to cause QT prolongation and is not approved for sale in Japan.

In addition, benzamide antipsychotics were not an independent risk factor for QTc prolongation in this study, and among them, only sulpiride was detected, which has not been frequently reported to cause QT prolongation [35,36]. Among the benzamide antipsychotics that likely cause QT prolongation and Tdp [10,27], amisulpride is not approved for sale in Japan, whereas sultopride was not detected in any patient in the present study. Therefore, the results of the present study do not allow us to evaluate the risk of QTc prolongation associated with overdose of benzamide antipsychotics other than sulpride.

The phenothiazine antipsychotics detected with toxic blood concen- tration in this study were levomepromazine, chlorpromazine, and promethazine. Overdose of these phenothiazine antipsychotics, unlike thioridazine and amisulpiride, has not been clearly proven to be a risk factor for TdP [24]. However, our present result demonstrates that over- dose of these drugs is also a risk factor for TdP.

There are a number of reports stating that use of an antidepressant causes QT prolongation [8,13-15]. In a study that analyzed ECGs of psy- chotropic Drug users, tricyclic/tetracyclic antidepressant users, amitrip- tyline users, maprotiline users, and nortriptyline users developed longer QTc than the nonusers [15]. In a study of adult patients prescribed either an antidepressant or methadone, SSRIs citalopram and escitalopram, as well as the tricyclic antidepressant amitriptyline, significantly influ- enced QTc prolongation, but this effect was not observed for any SNRI or NaSSA [13]. An investigation of patients with antidepressant over- dose using a QT nomogram and QTc as criteria demonstrated that the QT-heart rate pair was more likely to be significantly higher than the at-risk line of the QT nomogram, and QTc was more likely to be at least 440 milliseconds, in patients with citalopram overdose as com- pared with patients on other drugs, whereas the association of SNRI/ NaSSA overdose with these outcomes was not significant [14]. The above results suggest that tricyclic antidepressants, the SSRI citalopram, and analogous antidepressant drugs cause QT prolongation. In addition, trazodone, a nontricyclic/tetracyclic and non-SSRI/SNRI/NaSSA antide- pressant, is thought to be a drug relatively unlikely to cause QT prolon- gation, although it has been reported to cause QT prolongation at overdose levels in several cases [37]. Lithium users with prolonged QTc have been reported to have toxic lithium blood concentrations [15,38], whereas there have been no reports of TdP.

There are also a number of studies that have shown that sudden

death occurs more frequently in patients using an antidepressant [19-22]. In a study of patients with out-of-hospital cardiopulmonary ar- rest, 15.2% of the subjects were receiving antidepressant therapy at the onset of out-of-hospital cardiopulmonary arrest; citalopram was used by the greatest number of subjects (50.8%). Tricyclic antidepressants and SSRIs, particularly nortriptyline and citalopram, were risk factors for out-of-hospital cardiac arrest, whereas SNRIs and NaSSAs were not [21]. In addition, a systematic review of TdP cases showed many reports of oral ingestion of tricyclic/tetracyclic antidepressants amitriptyline and maprotiline [22]. However, in a case-control study of cases of sud- den death, the OR of sudden death was significantly higher with SSRIs, but not with tricyclic antidepressants [19]. Citalopram was the most ob- served SSRI in this study. These results suggest that users of a tricyclic/ tetracyclic antidepressant or an SSRI (citalopram and analogous drugs in particular) are more likely to develop QT prolongation and have a higher risk of sudden death, as compared with nonusers. In addition to their effects on IKr, tricyclic antidepressants have been reported to cause QT prolongation with wide QRS by blocking sodium/Calcium channels [22,39].

In the present study, a toxic blood concentration of a cyclic antide- pressant was an independent risk factor for QTc prolongation in patients with psychotropic drug overdose, but toxic concentrations of SSRIs, lith- ium, and other antidepressants (SNRIs, NaSSAs, trazodone) were not. In addition, a toxic blood concentration of a tricyclic antidepressant was a risk factor for a QT-heart rate pair higher than the at-risk line of the QT nomogram, whereas toxic concentrations of SSRIs, lithium, and other antidepressants (SNRIs, NaSSAs, trazodone) were not. Therefore, these results suggest that tricyclic antidepressant overdose increases the risk of TdP in drug overdose patients in the ED, but overdose of SSRIs, lithi- um, and other antidepressants, including SNRIs, NaSSAs, and trazodone, does not. Although citalopram and analogous drugs very likely increase the risk of QT prolongation and sudden death, toxic concentrations of SSRIs were not identified as risk factors for QT prolongation in this study because they were not detected in any patient.

This study has several limitations. The blood samples used for the measurement of drug blood concentrations and the ECGs used for the

measurement of QTc and QT-heart rate pairs were obtained on arriv- al at the ED, and thus evaluations were made at only 1 time point. Furthermore, an accurate time of drug ingestion was unknown for many patients, and drug pharmacokinetics was not examined. In addition, in the analysis using the QT nomogram, the confounding influence of other drugs that were concomitantly ingested could not be accounted for because there were only 35 patients with a QT-heart rate pair higher than the at-risk line of the QT nomogram. Moreover, because most of the subjects of this study were Japanese, the influence of race was not investigated.

Conclusions

When caring for patients with acute psychotropic drug overdose in the ED, the possibility of QT prolongation and TdP due to overdose of phenothiazine antipsychotic drugs levomepromazine, chlorpromazine, promethazine, or tricyclic antidepressants requires particular consider- ation. If overdose of any of these drugs is suspected, QTc should be mea- sured, and it should be repeatedly confirmed using Isbister’s QT nomogram method that the QT-heart rate pair is not higher than the at-risk line of the QT nomogram.

Table A.1 (continued)

Blood concentration

n.d Therapeutic range Toxic range

Barbiturate	549	69	31
Phenobarbital	551	67	31
Pentobarbital	645	4	0
Sodium valproate	575	54	20
Carbamazepine	632	8	9
Benzodiazepine	82	88	479
Lorazepam	599	43	7
Bromazepam	521	27	101
Alprazolam	564	52	33
Flunitrazepam	444	29	176
Etizolam	500	6	143
Nitrazepam	513	40	96
Flurazepam	647	0	2
Estazolam	607	12	30
Lormetazepam	637	0	12
Quazepam	623	22	4
Diazepam	570	32	47
Clonazepam	628	14	7
Brotizolam	582	14	53
Medazepam	648	0	1
Triazolam	614	14	21
Clotiazepam	635	7	7
Nonbenzodiazepine 518		34	97

Acknowledgments	Zopiclone	589	4	56
	Zolpidem	568	33	48

We thank Dr. Hiroyuki Kobayashi for his advice on the statisti- cal analysis.

Appendix

Alcohol (mg/dL) 3/4 100 N 100, 3/4 200 N 200

599 31 19

n.d., not detected.

Table A.1

Characteristics of study population

Blood concentration

n.d Therapeutic range Toxic range

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