Atypical antipsychotic medication poisoning: An evidence-based consensus guideline for out-of-hospital management

Figures & data

Table 1. Atypical antipsychotic medications available in the US, 2006 (3,4,6–9)

Generic name	Brand name(s)	Available formulations	Adult daily dosage range	Initial pediatricdoses (Ref.)
Aripiprazole	Abilify	2, 5, 10, 15, 20, 30 mg tablets	10–15 mg	Not available
		1 mg/mL oral solution	Concomitant CYP3A4 inducer use: 20–30 mg
		9.75 mg/1.3 mL single-dose vial for injection	9.75 mg
	Abilify Discmelt	10, 15 mg orally disintegrating tablets	10–15 mg
Clozapine	Clozaril	25, 100 mg tablets	12.5–900 mg	6.25–25 mg(125, 136)
Olanzapine	Zyprexa	2.5, 5, 7.5, 10, 15, 20 mg tablets	5–15 mgIn debilitated patients, those predisposed to hypotension, and slow metabolizers: 5 mg/d starting dosage	1.25 mg(212, 124, 126, 131)
		10 mg powder for injection/unit-dose vial	2.5–10 mg
	Zyprexa Zydis	5, 10, 15, 20 mg orally disintegrating tablets	5–15 mg
Quetiapine	Seroquel	25, 100, 200, 300, 400 mg tablets	25 mg twice daily up to 800 mg/d	Not available
			Patients with hepatic dysfunction: start at 25 mg/d
Risperidone	Risperdal	0.25, 0.5, 1, 2, 3, 4 mg tablets	1 mg twice daily up to 8 mg/d	0.125 mg (122–124, 127–130)
	Risperdal M-TAB	0.5, 1, 2, 3, 4 mg orally disintegrating tablets	Patients who are elderly, debilitated, predisposed to hypotension, or who have renal/hepatic impairment: 0.5–3 mg
	Risperdal Oral Solution	1 mg/mL oral solution
	Risperdal Consta	25, 37.5, 50 mg powder for injection/unit-dose vials	25–50 mg every 2 weeks
Ziprasidone	Geodon	20, 40, 60, 80 mg capsules	20 mg twice daily up to 160 mg/d	Not available
		20 mg powder for injection/unit-dose vial	10 mg every 2 hr or 20 mg every 4 hr up to 40 mg/d

*The cited studies enrolled patients as young as 3 years of age, with most starting at 4–5 years of age.

Table 2. Acute toxicity in patients less than 12 years of age

Drug	Dose	Age	Mitigating factors	Effect	Symptom onset^†	Confirm. Conc.?^‡	Ref. (LOE)
Aripiprazole	Description of 8 aripiprazole ingestions (avg. age 24 years, range 3–43) reported to a PC. Avg. dose was 82 mg. Three of 4 accidental ingestions were watched at home and all of the intentional ingestions were referred to EDs. Two intentional ingestions were admitted for excessive somnolence. All had “favorable outcomes.”						20 (4)
	15 mg [0.6 mg/kg]	9 yr	On amphetamine and valproic acid	Mod	3½ hr	NR	19 (4)
	20 mg [0.7 mg/kg]	6 yr	NR	Mod	>24 hours	NR	137 (4)
	∼11.9 mg [0.8 mg/kg] (based on calculation from serum drug conc.)	3 yr	NR	Mod	≤48 hr	B	21 (4)
	40 mg [2.4 mg/kg]	2 yr	NR	Mild	NR	NR	22 (6)
	195 mg [17.1 mg/kg]	3½ yr	NR	Mod/Severe	<1 hr	B	23 (4)
Clozapine	Description of 150 clozapine ingestions (143 adult and 7 pediatric) reported to the manufacturer or in the literature (some of these cases could therefore appear elsewhere in this summary); doses 50–25,000 mg; all of the children developed mild to severe clinical effects; lowest dose associated with severe toxicity in a child was <500 mg.						25 (4)
	100 mg [2.1 mg/kg]	10 yr	NR	Mod	<24 hr	U	27 (4)
	∼50 mg (one-half of a 100-mg tablet) [2.6 mg/kg]	21 mo	NR	Severe	NR	NR	Mady (4)
	100 mg [4.8 mg/kg]	4 yr	NR	Mod	∼1 hr	B	28 (4)
	100–200 mg [8.7–17.4 mg/kg]	31 mo	NR	Severe	<3 hr	B	28 (4)
	200 mg [10 mg/kg]	5 yr	NR	Severe	Soon after	B	29 (6)
	Description of 8 clozapine-only ingestions (ages 2–42 yr); doses 1100–5500 mg; >66% developed at least some clinical effects.						26 (4)
Olanzapine	Abstract of 12 olanzapine ingestions (11 adults and 1 child); doses 25–135 mg (7 cases had co-ingestants) in the adults; some developed mild–moderate effects.						62 (6)
	10 mg [0.6 mg/kg]	6 yr	Asthma	Mod	<15 hr	NR	30 (6)
	Up to 15 mg [0.9 mg/kg]	2½ yr	NR	Mod	≤10 hr	B	32 (6)
	30–40 mg [2.7–3.6 mg/kg]	18 mo	NR	Severe	<2 hr	B	33 (4)
	100 mg [3.4 mg/kg]	9 yr	Also ingested acetaminophen	Severe	≤2 hr	NR	31 (4)
Quetiapine	1300 mg [22.2 mg/kg]	11 yr	NR	Mod	<1 hr	NR	34 (4)
Risperidone	Abstract describing 31 risperidone ingestions (adult and pediatric); doses 1–150 mg (15 had co-ingestants); some developed clinical effects ranging from mild to moderate.						38 (6)
	1 mg [0.03 mg/kg]	7 yr	NR	Mod	NR	NR	36 (6)
	1 mg [0.07 mg/kg]	16 mo	NR	None	NR	NR	35 (4)
	4 mg [0.18 mg/kg]	5 yr	Clonazepam	None	NR	NR	35 (4)
	4 mg [0.3 mg/kg]	3½ yr	ADHD, on clonidine and methylphenidate chronically; missed a methylphenidate dose	Severe	NR	NR	37 (4)
Ziprasidone	Description of 30 ziprasidone ingestions (avg. age 23 years, range 1–41) reported to a PC. Avg. dose was 206 mg. Seven of 8 accidental ingestions were watched at home and all of the intentional ingestions were referred to EDs. One patient ingested an unknown dose and presented comatose, required intubation, and recovered after 8 hours. All others had “good outcomes.”						41 (6)
	Abstract describing 7 ziprasadone-only ingestions: a 22-m.o. ingested 40 mg [2.5 mg/kg] and a 2-y.o. ingested 80 mg [5.2 mg/kg]; only the 2 y.o. developed effects. The other children were more 10–16 yrs of age.						39 (6)
	400 mg	17 mo	NR	Mod	<1 hr	NR	40 (4)

*Mild = local effects only or mild systemic effects (e.g., sedated but arousable, agitated); mod = systemic effects (e.g., more severe sedation or agitation, tachycardia, hypertension, hyperthermia, ECG abnormalities); severe = life-threatening systemic effects (e.g., severe hyperthermia or rigidity, coma or sedation requiring intubation, seizures, respiratory depression, hypotension, dysrhythmias).

^†maximal time of onset; (i.e., symptoms were present on admission, but might have begun earlier).

^‡B = blood.

NR = not reported or none reported.

Table 3. Acute toxicity in patients 12 years of age and older

Drug	Dose	Age (yr)	Mitigating factors	Effect	Symptom onset^†	Confirm. Conc.?^‡	Ref. (LOE)
Aripiprazole	Description of 8 aripiprazole ingestions (avg. age 24 years, range 3–43) reported to a PC. Avg. dose was 82 mg. Three of 4 accidental ingestions were watched at home and all of the intentional ingestions were referred to EDs. Two intentional ingestions were admitted for excessive somnolence. All had “favorable outcomes.”						41 (4)
	330 mg	27	Also ingested 25 mg of quetiapine	Mod	≤50 min	B (Aripip only)	42 (4)
Clozapine	Description of 150 clozapine ingestions (143 adult and 7 pediatric) reported to the manufacturer or in the literature (some of these cases may therefore appear elsewhere in this summary); doses 50–25,000 mg; some adult patients developed mild to severe clinical effects; lowest dose associated with severe toxicity in an adult was <500 mg.						25 (4)
	Description of 7 clozapine ingestions (ages 22–48 yr); doses 100–16,000 mg; some developed clinical effects ranging from mild to severe; lowest dose associated with mild effects was 100 mg, lowest dose associated with severe toxicity in an adult was 1000 mg.						43 (4)
	100 mg	16	NR	Mod	NR	B	48 (6)
	100 mg	16	Urine positive for THC	Mod	NR	B	48 (6)
	100 mg dissolved in tea	Middle-age	NR	Severe	<2 hr	B	Browne (4)
	800 mg	31	NR	Severe	<1 hr	B	47 (4)
	1000 mg	50	On chronic clozapine	Mod	NR	NR	49 (6)
	Description of 8 clozapine-only ingestions (ages 2–42 yr); doses 1100–5500 mg; >66% developed at least some clinical effects.						26 (4)
	2000 mg	33	? on clozapine chronically	Mod	<20 hr (obtundation ∼72 hr)	NR	52 (4)
	∼2000 mg	25	Recently started on clozapine; cardiomegaly and left ventricular hypertrophy on autopsy	Death	<3¼ hr	NR	50 (6)
	2250 mg	33	NR	Mod	<2½ hr	B	60 (6)
	3000 mg	26	History of alcoholism, and sleeping problems for which he had been prescribed clozapine	Mod	NR	NR	56 (4)
	3000 mg	29	Also ingested 150 mg zopiclone, alprazolam, and alcohol; possible ingestion of another benzodiazepine	Severe	<1–2 hr	B	44 (4)
	3000–4000 mg	40	On chronic insulin, clozapine, loxapine, and procyclidine	Severe	NR	B	53 (4)
	∼3500 mg	20	On chronic flupenthixol, valproate, cloanzepam, and lorazepam; may also have ingested clonazepam	Severe	<6 hr	B	58 (4)
	≤3750 mg	29	History of substance abuse and psychiatric disorders	Severe	≤12–24 hr	B	59 (4)
	5000 mg	19	On chronic clozapine	Mod	∼2½ hr	B	45 (4)
	6000–8000 mg	34	On chronic clozapine	Severe	<1 hr	B	51 (4)
	7300 mg	24	On chronic clozapine, moclobemide, and lithium	Severe	<12 hr	NR	54 (4)
	12,500 [∼122 mg/kg]	41	On clozapine chronically	Mod	≤42–46 hr	B	55 (4)
Olanzapine	Abstract of 12 olanzapine ingestions (11 adults and 1 child); doses 25–135 mg (7 cases had co-ingestants) in the adults; some developed mild–moderate effects.						62 (6)
	Description of 26 olanzapine ingestions (all patients >16 yr); doses 30–830 mg (no co-ingestants); some developed clinical effects ranging from mild to severe; lowest dose associated with mild toxicity was 30 mg; lowest dose associated with moderate toxicity was 120 mg; lowest dose associated with severe toxicity was 560 mg.						61 (4)
	Description of 11 olanzapine-only ingestions (ages 18–33 yr); doses 50–1400 mg; >66% developed at least some clinical effects ranging from mild to severe.						Capel (4)
	75 mg	17	Also ingested prazepam; on prazepam and olanzapine chronically	Mod	NR	NR	68 (6)
	Smoked 20 tablets	24	Also smoked marijuana	Severe	NR	B	78 (6)
	∼115 mg	15	History of seizures and depression; either on carbemazepine chronically, or acutely ingested it	Severe	NR	NR	67 (6)
	120 mg	38	On chronic olanzapine	Mild	NR	NR	66 (4)
	150 mg	38	On chronic olanzapine	Severe	<30 min	B	74 (4)
	30 tablets	33	NR	Mod	NR	NR	71 (6)
	200 mg	48	NR	Mod	≤2 hr	NR	67 (6)
	210 mg	12	On chronic olanzapine, paroxetine, and dextroamphetamine/amphetamine	Mod	≤30 min	B	115 (4)
	300 mg	25	On chronic trazadone and olanzapine	Mod	<2 hr	U	72 (6)
	300 mg	33	NR	Mod	NR	U	75 (6)
	350 mg	50	Also ingested alcohol and 70 mg of clonazepam	Mod	<1 hr	B	73 (6)
	Up to 600 mg	31	NR	Severe	NR	B	69 (4)
	As much as 600 mg over ∼4 hr	43	Psychiatric problems; cirrhosis; ethanol, diphenhydramine, and trazodone found in blood at autopsy	Death	<10 hr	B (postmortem)	76 (4)
	700 mg	37	Also ingested venlafaxine	Severe	NR	B	63 (4)
	∼700 mg	36	On sertraline and olanzapine chronically	Mod	NR	“Quantitative testing”	77 (6)
	∼750 mg	62	On chronic olanzapine, lithium, ibuprofen, terazosin, rabeprazole, methocarbamol, and thiamine	Death	NR	B	65 (4)
	800 mg	22	On olanzapine chronically	Mod	∼3 hr	B	64 (4)
	1000 mg	44	On olanzapine chronically	Severe	NR	B	74 (4)
	>1000 mg	55	NR	Severe	NR	B	73 (6)
	1110 mg [11.3 mg/kg]	29	NR	Severe	≤1 hr	NR	70 (4)
Quetiapine	Abstract describing 17 adult quetiapine ingestions; doses ≤8000 mg (13 cases had co-ingestants); some developed clinical effects ranging from mild to moderate/severe.						80 (6)
	25 mg	27	Also ingested 330 mg of aripiprazole	Mod	≤50 min	B (Aripip)	42 (4)
	675 mg	45	On chronic quetiapine, carbamazepine, and fluoxetine	Mod (priapism)	The next day	NR	90 (4)
	Prospectively collected data on 18 patients with confirmed quetiapine OD admitted to hospital; doses, when known, 500–24,000 mg; some developed effects ranging from mild to severe effects (12 had co-ingestants); among the 6 patients ingesting quetiapine alone, the minimum dose resulting in any effects was 800 mg, while the minimum dose resulting in seizures/hypotension was 24,000 mg.						79 (2b)
	1000 mg	50	Also ingested ziprasidone 1760 mg	Mod	<1 hr	NR	40 (4)
	1250 mg	15	NR	Mod	<2 hr	B	82 (4)
	1900 mg [26 mg/kg]	14	On mirtazipine and quetiapine chronically	Mod	<30–60 min	NR	88 (4)
	∼2000 mg [15.4 mg/kg]	31	On chronic quetiapine, risperidone, clonazepam, topiramate, venlafaxine	Mod	<2 hr	B	81 (4)
	3000 mg	40	On chronic chloral hydrate, valproic acid, quetiapine, and clonazepam	Mod	<1 hr	B	91 (4)
	4700 mg	21	On chronic quetiapine and fluoxetine; also ingested 600 mg fluoxetine	Mod	NR	B	89 (4)
	5400 mg	30	NT	Severe	NT	NT	84 (6)
	Nearly 8000 mg	29	Also ingested ethanol	Severe	≤1 hr	B	93 (6)
	9600 mg	19	NR	Severe	<2 hr	NR	87 (4)
	>10,000 mg	26	NR	Severe	2½ hr	NR	85 (4)
	∼10,800 mg	52	Also on chronic felodipine, buspirone, sertraline, quetiapine and IM haloperidol; history of cardiac dysrhythmias and hypertension	Death	NR	B (postmortem)	83 (4)
	12,000 mg	19	On valproic acid and acetaminophen chronically	Severe	<2½ d	B	94 (4)
	∼14,000 mg	19	On chronic divalproex, gabapentin, and sertraline	Mod/Severe	≤5 hr	NR	95 (4)
	15,000 mg	36	NR	Severe	NR	NR	86 (6)
	20,000 mg	38	Also ingested 16 g valproate; on quetiapine, valproate, chloridemethyl-diazepam, and venlafaxine chronically	Severe	<4–5 hr	NR	92 (4)
Risperidone	Abstract describing 31 risperidone ingestions (adult and pediatric); doses 1–150 mg (15 had co-ingestants); some developed clinical effects ranging from mild to moderate.						38 (6)
	Abstract describing 6 adult risperidone ingestions; doses 5–270 mg (2 had co-ingestants); some developed clinical effects ranging from mild to moderate.						96 (6)
	Letter describing 117 risperidone ingestions; 32 ingested risperdione alone; doses 5–240 mg; some developed clinical effects ranging up to moderate.						97 (6)
	∼14 mg [0.3 mg/kg]	34	On risperidone, biperiden, and flunitrazepam chronically	Severe	<1 hr	B	107 (4)
	Description of 10 risperidone-only ingestions (ages 28–63 yr); doses 16–210 mg; <33% developed clinical effects, ranging from mild to moderate						26 (4)
	21 mg [0.41 mg/kg]	16	Also on Provera; prior methylphenidate use	Mod	<30 min	NR	103 (4)
	24 mg [0.41 mg/kg]	16	NR	Mod	∼5 min	NR	103 (4)
	40 mg	15	NR	Severe	<1½ hr	NR	102 (4)
	Summary of 31 risperidone ingestions (29 adults/adolescents and 2 children); adult/adolescent doses 21–180 mg (cases with co-ingestants excluded); some developed clinical effects ranging from mild to severe.						35 (4)
	∼90 mg [1.2 mg/kg]	45	On risperidone, brotizolam, zopiclone, nitrazepam, haloperidol, and promethazine; possible co-ingestion of other medications	Severe	≤12 hr	B	107 (4)
	100 mg	21	Schizophrenia, on chronic risperidone, paroxetine, and estazolam; possible co-ingestion of paroxetine based on serum conc.	Mod	<4 hr	B	104 (4)
	110 mg [1.7 mg/kg]	15	Also drank wine and smoked marijuana	Mod	<3 hr	B	99 (4)
	120 mg	39	NR	Mod	≤5 hr	NR	100 (4)
	120 mg [1.5 mg/kg]	21	NR	Mod	<2 hr	NR	105 (4)
	228 mg	35	NR	Mod	<20 min	NR	106 (4)
	240 mg	29	NR	Mod	<45 min	NR	98 (4)
	270 mg	41	On risperidone chronically; intermittent benzodiazepine use	Severe	≤3 hr	NR	101 (4)
	≤403 mg	45	Schizophrenic; possible ingestion of buspirone	Death	NR	B (postmortem)	108 (4)
Ziprasidone	Description of 30 ziprasidone ingestions (avg. age 23 yr, range 1–41) reported to a PC. Avg. dose was 206 mg. 7 of 8 accidental ingestions were watched at home; all of the intentional ingestions were referred to EDs. One patient ingested an unknown dose and presented comatose, required intubation, and recovered after 8 hours. All others had “good outcomes.”						41 (6)
	Abstract describing 7 pediatric ziprasadone-only ingestions (5 were 10–16 yr old); doses 60–360 mg; some developed clinical effects ranging from mild to moderate.						39 (6)
	Abstract describing 26 adult ziprasadone-only ingestions; doses 180–4020 mg were reported; some developed clinical effects ranging from mild to severe						109 (6)
	1040 mg	50	? on ziprasadone chronically	Mod (QTc prolongation)	6–10 hr	NR	22 (6)
	1200 mg	37	Also ingested heroin and cocaine; urine toxicology positive for opiates, benzodiazepines and methadone	Mod	<4 hr	NR	40 (4)
	1760 mg	50	Also ingested quetiapine 1000 mg	Mod	<1 hr	NR	40 (4)
	3120 mg	50	NR	Mod	<4½ hr	NR	110 (4)
	4020 mg	38	On chronic quetiapine, gabapentin, venlafaxine, metformin, rofecoxib, pravastatin	Mod/Severe	<6 hr	NR	111 (4)

*Mild = local effects only or mild systemic effects (e.g., sedated but arousable, agitated); mod = systemic effects (e.g., more severe sedation or agitation, tachycardia, hypertension, hyperthermia, ECG abnormalities); severe = life-threatening systemic effects (e.g., severe hyperthermia or rigidity, coma or sedation requiring intubation, seizures, respiratory depression, hypotension, dysrhythmias).

^†maximal time of onset; (i.e., symptoms were present on admission, but might have begun earlier).

^‡B = blood, U = urine.

NR = not reported or none reported.

NT = not fully translated.

Table

Grade ofrecommendation	Level of evidence	Description of study design
A	1a	Systematic review (with homogeneity) of randomized clinical trials
	1b	Individual randomized clinical trials (with narrow confidence interval)
	1c	All or none (all patients died before the drug became available, but some now survive on it; or when some patients died before the drug became available, but none now die on it.)
B	2a	Systematic review (with homogeneity) of cohort studies
	2b	Individual cohort study (including low quality randomized clinical trial)
	2c	“Outcomes” research
	3a	Systemic review (with homogeneity) of case-control studies
	3b	Individual case-control study
C	4	Case series, single case reports (and poor quality cohort and case control studies)
D	5	Expert opinion without explicit critical appraisal or based on physiology or bench research
Z	6	Abstracts

3. Abilify [package insert]. New York, NY: Bristol-Meyers Squibb, 2006.

 Google Scholar

4. Clozaril [package insert]. Basel: Novartis Pharmaceuticals, 2005.

 Google Scholar

Devinsky O, Honigfeld G, Patin J. Clozapine-related seizures. Neurology 1991; 41: 369–371

 PubMed Web of Science ®Google Scholar

McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, Arnold LE, Lindsay R, Nash P, Hollway J, McDougle CJ, Posey D, Swiezy N, Kohn A, Scahill L, Martin A, Koenig K, Volkmar F, Carroll D, Lancor A, Tierney E, Ghuman J, Gonzalez NM, Grados M, Vitiello B, Ritz L, Davies M, Robinson J, McMahon D. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002; 347: 314–321

 PubMed Web of Science ®Google Scholar

Croonenberghs J, Fegert JM, Findling RL, De Smedt G, Van Dongen S. Risperidone in children with disruptive behavior disorders and subaverage intelligence: A 1-year, open-label study of 504 patients. J Am Acad Child Adolesc Psychiatry 2005; 44: 64–72

 PubMed Web of Science ®Google Scholar

Findling RL, Maxwell K, Wiznitzer M. An open clinical trial of risperidone monotherapy in young children with autistic disorder. Psychopharmacol Bull 1997; 33: 155–159

 PubMed Web of Science ®Google Scholar

Kumra S, Frazier JA, Jacobsen LK, McKenna K, Gordon CT, Lenane MC, Hamburger SD, Smith AK, Albus KE, Alaghband-Rad J, Rapoport JL. Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry 1996; 53: 1090–1097

 PubMed Web of Science ®Google Scholar

6. Zyprexa [package insert]. Indianapolis, IN: Eli Lilly & Co, 2006.

 Google Scholar