Fatal Overdoses Associated with Quetiapine

Abstract

Quetiapine (Seroquel) is an atypical antipsychotic drug belonging to a new chemical class, the benzothiazepine derivatives. We present three cases from the Provincial Toxicology Center of British Columbia, Canada in which suicidal overdose deaths were associated with quetiapine. The blood specimens were initially subjected to a thorough qualitative analysis. Basic drugs were screened for by liquid-liquid extraction followed by gas chromatography-nitrogen-phosphorus (GC-NPD) and gas chromatography-mass spectrometry-electron impact detection utilizing both in-house and commercial search libraries. Acidic and neutral drugs were screened for by liquid-liquid extraction followed by high-performance liquid chromatography-diode-array detection. Volatiles were assayed by gas chromatography-flame-ionization detection. Quetiapine was assayed in biological specimens by basic extraction with n-butyl chloride and derivatized with 50 microL of MTBSTFA and separation by GC-NPD. Linearity was observed up to 2.0 mg/L. Samples with concentrations exceeding the linearity were diluted. These cases were chosen for study because they were all deaths as a result of suicidal ingestion of drugs in which quetiapine was considered a significant factor. The concentrations of quetiapine in these cases are 6-16 times greater than the upper reported therapeutic range (0.1-1.0 mg/L). In case #1, the concentrations of quetiapine found were 7.20 mg/L (19 micromol/L) in blood and 0.93 mg/L (2.4 micromol/L) in vitreous fluid. In case #2, the concentrations of quetiapine found were 16 mg/L in blood (42 micromol/L), 120 mg/kg (310 micromol/kg) in liver, and 1.8 mg/L (4.6 micromol/L) in vitreous fluid. In case #3, the concentrations of quetiapine found in femoral blood was 5.90 mg/L (15 micromol/L). In all cases, drugs in addition to quetiapine were detected, but in cases #1 and #2, the cause of death was considered to be a quetiapine overdose and the other drugs were not considered to be contributory. Case #3 was considered a mixed drug overdose.

Late-onset seizures associated with quetiapine poisoning

“…The reported therapeutic range of quetiapine is 0.1 to 1.0 mg/L [3,4]. However, plasma quetiapine levels and clinical response do not correlate.…”

“…Quetiapine fumarate (Seroquel) is an atypical antipsychotic that antagonizes cerebral serotonergic 5-HT1A, 5-HT2, dopaminergic D1 and D2, histaminic H1, muscarinic M1, and adrenergic ␣-1 and ␣-2 receptors [3,4]. It is rapidly absorbed orally, attains peak plasma concentration in 1-2 hours, is metabolized by liver cytochrome p450 3A4 isoenzyme to the active metabolite 7-hydroxyquetiapine, and is excreted primarily in the urine [1,4,5].…”

“…The serum quetiapine levels (MedTox, St. Paul, MN) were 8.67 mg/L on hospital day 1 and 3.28 mg/L on hospital day 3. Therapeutic levels have been reported as 0.1 to 1.0 mg/L [3]. On hospital day 4, the patient was more alert, followed commands, and was extubated.…”

A validated GC/MS method for the investigation of quetiapine-related deaths in Greece

“…The drug was approved by the United States Food and Drug Administration (FDA) in 1997, for the treatment of psychotic disorders [3,4]. Quetiapine is used to treat the symptoms of patients suffering from schizophrenia, bipolar disorder and major depressive disorder, under the trade name Seroquel ® (AstraZeneca) [5,6]. There is also evidence that quetiapine may benefit patients diagnosed with a mental illness who are also dependent on alcohol [7][8][9], cocaine [5,7,9], amphetamines [9,10], and for the reduction of opioid withdrawal symptoms [11].…”

“…The drug is also strong antagonist at histamine H 1 , adrenergic α 1 and α 2 receptors [24]. The most frequently reported and clinically significant side effects of quetiapine use include dizziness, orthostatic hypotension, tachycardia, somnolence, weight gain, dry mouth, and dyspepsia [6]. Potentially, life-threatening consequences from quetiapine overdose include QT prolongation, loss of consciousness, sinus tachycardia, hypokalemia with first degree heart block, and respiratory depression that could result in lethal ventricular arrhythmias [14,25].…”