Survival from coma induced by an intentional 36-g overdose of extended-release quetiapine

Quetiapine is a second-generation antipsychotic drug approved for the treatment of bipolar disorders and schizophrenia. Acute quetiapine overdose is rare, and quetiapine has long been thought to be safer than other antipsychotics. Nevertheless, as reported in the literature, the severity of the effect of quetiapine overdose has not been associated with a high serum concentration of the drug or with the reported ingested dose. In this article, we report a case of survival from coma induced by a massive extended-release (XR) quetiapine ingestion at a dose greater than reported in some previous fatal cases. A 34-year-old woman with chronic schizophrenia ingested 36?g of quetiapine fumarate XR for attempted suicide. She was initially lethargic, but her clinical conditions rapidly deteriorated and she collapsed unconscious. The woman was taken to the nearest hospital, where the medical emergency team found her in deep coma with response only to deep painful stimuli (Glasgow Coma Scale 9). An endotracheal tube was inserted for airway protection, and the patient was transferred to a critical care area for ventilatory support and maintenance of hydration status and electrolytic balance. Spontaneous breathing was restored in approximately 36 hours, and a few days later, she was discharged without reporting clinical complications. This is the first case of coma induced by an intentional 36-g overdose of quetiapine XR. Given the widespread use of quetiapine and the lack of information about its toxicity in overdose, this case report reinforces the importance of closely monitoring patients taking quetiapine and helps to better define the safety of this drug.     

Quetiapine cross-reactivity among three tricyclic antidepressant immunoassays

Quetiapine is an atypical antipsychotic agent with structural similarities to the tricyclic antidepressants (TCA). We report a case of quetiapine overdose that was initially clinically similar to that of a TCA overdose and caused a false-positive TCA immunoassay. We then analyzed three common TCA immunoassays [Microgenics (formerly Diagnostic Reagents, Inc.) Tricyclics Serum Tox EIA Assay, Syva RapidTest d.a.u., and Biosite Triage Panel for Drugs of Abuse] with quetiapine in solution as well as urine from both an overdose patient and a therapeutic patient. There was significant variation of the cutoff of false-positivity in all three immunoassays. Both the Syva and Microgenics immunoassays tested positive in both the overdose and therapeutic samples and were positive at urine levels of 100 microg/mL and 10 microg/mL, respectively. The Triage immunoassay was negative in solutions up to 1000 microg/mL and negative in both the therapeutic and overdose urine samples. Quetiapine may cause false-positive TCA immunoassay with both therapeutic use and in overdose. Significant variation exists between immunoassays to detect quetiapine as a false-positive test.     

Acute quetiapine overdose in an eleven-year-old girl

We present a case of acute Quetiapine (SeroQuel) overdose in an 11-y-old girl who ingested 1,300 mg (22.2 mg/kg bw). Initial lethargy developed within I h followed by an episode of agitation and combativeness 3 h after ingestion. After treatment with lorazepam the patient experienced extended somnolence followed by return to normal mental status 16 h after ingestion. No cardiotoxic or laboratory abnormalities were found. This is the first report of acute Quetiapine overdose in an adolescent and suggests a relatively benign clinical course.     

Baclofen intoxication after accidental ingestion in a 3-year-old child

Baclofen is a skeletal muscle relaxant, used to control spasticity in both adults and children with neuromuscular disorders. Several cases of baclofen overdose have been reported, but only a small number have involved children. We report a 3-year-old girl with accidental ingestion of baclofen, who presented with coma, bradycardia and hypotension. She recovered within 24 hours with supportive treatment. The case emphasizes the importance of warning parents about the potential toxicity of baclofen when the drug is prescribed to a family member.     

Lactic acidosis, hypotension, and sensorineural hearing loss following intentional metformin overdose

Metformin and glyburide are antihyperglycemic agents that are widely used in the United States. There have been several cases of overdose of these medications reported in the world literature. Glyburide overdose is associated with hypoglycemia that can be severe, while metformin overdoses have been associated with lactic acidosis. In many cases of metformin overdose, lactic acidosis has led to profound hypotension and respiratory failure. In this article we will present the case of a 49-year-old man who ingested 52 grams of metformin and 350 mg of glyburide in a suicide attempt. The patient developed hypoglycemia, lactic acidosis, hypotension, respiratory failure and a profound sudden sensorineural hearing loss. We discuss prior cases of overdose with these agents, and the connection between overdose and the development of sudden sensorineural hearing loss.     

A fatal overdose of carbamazepine: case report and review of literature

Carbamazepine is a drug of choice for partial epilepsies, certain affective disorders and neuralgic pain syndromes. It has an excellent safety record; however, overdose can be dangerous. This article reports one of the very few fatalities from carbamazepine overdosage, in an individual with a peak carbamazepine level of 54 mg/L. Manifestations of this and other major carbamazepine overdoses reviewed from the literature were similar to those of tricyclic - anticholinergic overdose, with coma, hypotension, respiratory depression, cardiac arrhythmias, abnormal movements and seizures. Fatality from cardiovascular causes occurred despite decline of serum carbamazepine levels to the putatively non-toxic range, emphasizing the potential for delayed consequences of carbamazepine overdosage. Management should consist of vigorous gastric lavage and installation of activated charcoal, full supportive care in a monitored setting and consideration of early charcoal hemoperfusion, before the patient becomes hypotensive.     

Acute oxcarbazepine and atomoxetine overdose with quetiapine

We present a case of acute oxcarbazepine and atomoxetine overdose combined with excess quetiapine in a 19-y-old male. The patient ingested approximately 36 g oxcarbazepine (514 mg/kg), 1.2 g atomoxetine (17 mg/kg), and 9 mg Quetiapine (128 mg/kg). Central nervous system (CNS) depression with initial unresponsiveness developed within 1 h of ingestion, necessitating intubation for airway protection. Despite aggressive therapy with whole bowel irrigation and charcoal administration, the patient's somnolence persisted for 4 d, punctuated by occasional violent outbursts. Prolonged QTc was noted initially, but normalized within 4 d. This case suggests that acute overdose of oxcarbazepine and atomoxetine combined with quetiapine is associated with rapid and prolonged CNS depression.     

Prolonged coma and loss of brainstem reflexes following amitriptyline overdose

Severe tricyclic antidepressant (TCA) overdose is generally manifested by cardiovascular and/or central nervous system toxicity. Although the majority of patients who are comatose following these overdoses regain consciousness within 24 h, this case had 5-days of coma with associated loss of brainstem reflexes. Severe central nervous system depression can occur as a sole manifestation of TCA overdose without concomitant cardiovascular toxicity.     

Prolonged toxicity after massive olanzapine overdose: two cases with confirmatory laboratory data

Olanzapine is a second-generation atypical antipsychotic that is increasingly used in preference to older antipsychotic agents. Limited data is available concerning the toxic effects of olanzapine after deliberate overdose. Two patients presented to our institution after massive olanzapine ingestion, and required prolonged ventilatory support due to the development of coma and respiratory depression. Serum olanzapine concentrations were orders of magnitude higher than those associated with therapeutic doses, and remained elevated for several days after ingestion. Both patients made a full recovery with only supportive care, despite having initial serum drug concentrations > 2500 microg/l. These reports indicate the potential for olanzapine ingestion to cause coma that may persist for several days after overdose.     

Clinical experience with the benzodiazepine antagonist flumazenil in suspected benzodiazepine or ethanol poisoning

The clinical efficacy of different doses of the specific benzodiazepine antagonist flumazenil was studied in a total of 72 patients with benzodiazepine or ethanol overdose. In a randomized double-blind study, 18 patients (group 1) and eight patients (group 2) with suspected benzodiazepine overdose received 5 mg (group 1) or 1 mg (group 2) flumazenil or placebo, respectively. The stage of coma, heart rate, blood pressure and respiratory rate were monitored within the following 15 min. If no change in the stage of coma was observed, 5 mg (group 1) or 1 mg (group 2) flumazenil were given, and the stage of coma, heart rate and blood pressure were again monitored. In a similar way, the effect of 5 and 1 mg flumazenil was investigated in 13 patients (group 3) and four patients (group 4) with ethanol intoxication. In an open trial, the clinical efficacy of flumazenil for the diagnosis of benzodiazepine or ethanol overdose was studied in 29 patients (group 5). In all patients, a toxicological screening confirmed benzodiazepine or ethanol overdose. None of the patients receiving placebo showed effects on stage of coma, heart rate, blood pressure or respiratory rate. Patients with benzodiazepine overdose who received 5 mg flumazenil regained consciousness about 1-2 min after the end of injection. The effect of 1 mg flumazenil (group 2) on benzodiazepine-induced coma was less pronounced. In patients with ethanol overdose (group 3), ethanol-induced coma was reversed after 5 mg flumazenil more slowly than in patients of group 1. No effect of flumazenil on ethanol-induced coma was observed in group 4. In group 5, flumazenil proved to be useful for diagnosing benzodiazepine or ethanol intoxication. In one patient with coma due to carbamazepine overdose, flumazenil was also found to be effective. Additionally, a possible analytical interference of flumazenil and its metabolites with the identification of other benzodiazepines by a toxicological screening procedure was studied. Even after an oral dose of 200 mg flumazenil, no interference with immunological benzodiazepine assays (EMIT, TDX, and RIA) was found. A metabolite and an artifact of flumazenil could be identified in urine by gas chromatography/mass spectrometry.     

Late-onset seizures associated with quetiapine poisoning

Introduction

Quetiapine, a second-generation antipsychotic, acts at multiple brain neurotransmitter receptors and has the potential for serious complications. Although seizures have been described in the literature, delayed seizure onset has not been reported. We report the first case of delayed seizures after a significant quetiapine overdose.

Case Report

A 27-year-old female presented to the emergency department following an overdose of approximately 30 g of quetiapine. Twenty-four hours after arrival, the patient had 2 seizures. The patient was then intubated and remained in the ICU for four days. EEG was negative for epileptiform activity. The serum quetiapine levels (MedTox, St. Paul, MN) were 8.67 mg/L on hospital day one and 3.28 mg/L on hospital day three.

Discussion

Quetiapine poisoning, with serum levels, associated with seizures has been reported in one prior case. Our case report represents late-onset seizures with serum levels above therapeutic range (> 1 mg/L). The serum concentrations of quetiapine in this case were consistent with those in postmortem case reports.     

Retrospective review of Tizanidine (Zanaflex) overdose

BACKGROUND: Tizanidine is a centrally acting muscle relaxant with a novel mechanism of action and structurally related to clonidine. There are no large case series of tizanidine exposure. METHODS: Retrospective review of all ingestions involving tizanidine reported to a poison control center from January 2000 through February 2003. Exclusion criteria were polydrug ingestion, no follow-up or lost to follow-up. RESULTS: There were 121 cases of which 45 patients met entrance criteria. Mean age was 32 years (range 1 to 80). Thirty-seven patients were evaluated in a health care facility of which 27 were admitted for medical care. Clinical effects included lethargy (n = 38), bradycardia (n = 14), hypotension (n = 8), agitation (n = 7), confusion (n = 5), vomiting (n = 3), and coma (n = 2). Mean dose ingested by history was 72 mg (S.D. + 86). The lowest dose associated with hypotension was 28mg, which occurred in a 63-year-old female with a BP of 88/52 and a HR of 54. The lowest dose associated with coma was between 60 mg and 120 mg, which occurred in a 30-year-old female with a HR of 30 and BP of 81/48. There were 6 patients < 6 yrs. The lowest dose with bradycardia and drowsiness in a small child was 16 mg in a 2 YO (weight unknown). All other cases in children < 6 yrs involved ingestion of a single tablet (2 or 4 mg) with only mild drowsiness reported. Therapy in this series was primarily supportive and included pressors in 3 cases and intubation in 3 cases. Naloxone was administered to 7 patients. There was no response to naloxone in 5 patients, poor documentation of response in one, and arousal in one patient. All patients recovered without residual complications. CONCLUSION: Clinical manifestations of tizanidine overdose include alterations of mental status, bradycardia, and hypotension. In this series, outcome was good with supportive therapy.     

Predicting severity of tricyclic antidepressant overdose.

The measurement of plasma concentration, a prolonged QRS interval, and level of consciousness have all been recommended as useful indicators of toxicity following tricyclic antidepressant overdose. The aims of this study were firstly, to determine the relative prognostic value of each of these indicators and secondly, to assess when a patient can be discharged safely from the intensive care unit. Data were evaluated on 67 patients with tricyclic antidepressant overdose from four centers. Plasma tricyclic antidepressant concentrations were measured, coma grade was evaluated using the Matthew-Lawson Coma Scale and a ECG was obtained from 23 patients on admission. Complications such as convulsions, hypotension, arrhythmias, and need for intubation and ventilation were recorded. Thirty patients developed complications and no patient died. Coma grade was the best predictor of outcome. The development of serious complications is unlikely in patients whose level of consciousness is grade II or less and who are admitted to hospital more than 6 h after overdose. Plasma tricyclic antidepressant concentration was of no additional value in predicting toxic complications or deciding when the patient could leave the intensive care unit. Our study suggests that an alert and orientated patient with a QRS duration less than 100 ms is the best indicator for safe transfer to a medical or psychiatric ward.     

Treatment of poisoning caused by beta-adrenergic and calcium-channel blockers.

PURPOSE: The toxic effects and treatment of beta-adrenergic blocker and calcium-channel blocker (CCB) overdose are reviewed. SUMMARY: Overdoses with cardiovascular drugs are associated with significant morbidity and mortality. Beta-blockers and CCBs represent the most important classes of cardiovascular drugs. In overdose, beta-blockers and CCBs have similar presentation and treatment overlaps and are often refractory to standard resuscitation measures. The common feature of beta-blocker toxicity is excessive blockade of the beta-receptors resulting in bradycardia and hypotension. Poisoning by CCBs is characterized by cardiovascular toxicity with hypotension and conduction disturbances, including sinus bradycardia and varying degrees of atrioventricular block. Therapies include beta-agonists, glucagon, and phosphodiesterase inhibitors. However, in beta-blocker poisoning where symptomatic bradycardia and hypotension are present, high-dose glucagon is considered the first-line antidote. Traditionally, antidotes for CCB overdose have included calcium, glucagon, adrenergic drugs, and amrinone. For cases of CCB poisoning where cardiotoxicity is evident, first-line therapy is a combination of calcium and epinephrine; high-dose insulin with supplemental dextrose and potassium therapy (HDIDK) is reserved for refractory cases. Health-system pharmacists should be aware that when these drugs are used as antidotes, higher than normal dosing is needed. CONCLUSION: Poisoning by beta-blockers or CCBs usually produces hypotension and bradycardia, which may be refractory to standard resuscitation measures. For cases of beta-blocker poisoning where symptomatic bradycardia and hypotension are present, high-dose glucagon is considered the first-line antidote. For cases of CCB poisoning where cardiotoxicity is evident, a combination of calcium and epinephrine should be used initially, reserving HDIDK for refractory cases.     

Use of promethazine,gabapentin and clonidine in combination with opioids or opioid agonist therapies among individuals attending a syringe service program

Background: Clonidine, gabapentin, and promethazine are commonly used by people who use opioids, including heroin, raising concern for increased morbidity and mortality in a vulnerable population. We aimed to characterize how and why individuals use opioids in combination with these three psychoactive medications (PAMs). Methods: Participants (n = 103) were a convenience sample of adults attending a syringe service program who reported using a PAM in addition to opioids or opioid agonist therapies (buprenorphine or methadone). Face-to-face structured interviews consisted of closed and open-ended questions. Results: Patterns of PAM use varied. Risky use, including use of high doses and with other sedating medications, was common. Most individuals reported multiple medical reasons for use, even while reporting the PAM had mind-altering effects. Use of high doses of PAMs was associated with a history of overdose. Among those with a history of overdose, 32% reported that a PAM was involved. Conclusion: The use of clonidine, gabapentin and promethazine among individuals who use opioids is complex. Providers should take individualized approaches to PAM prescribing, recognizing both the risks of PAMs and the potential unintended consequences of supply-side interventions in the era of the overdose crisis. Harm reduction interventions are needed to prevent PAM-involved overdoses.     

Demographic and electrocardiographic factors associated with severe tricyclic antidepressant toxicity

This study was designed to evaluate a historic cohort of pure tricyclic antidepressant overdose patients for factors associated with severe toxicity. Hospitalized tricyclic antidepressant overdose patients were identified by computerized discharge diagnosis (ICD-9 codes). Patients with a serum drug screen positive for tricyclic antidepressants and an emergency department 12-lead electrocardiogram were included in the study. Multiple drug overdoses were excluded. Patients were divided into two groups: minor toxicity (n = 41 and major toxicity (n = 65). Criteria for inclusion in the major toxicity group were the occurrence of seizures, endotracheal intubation, coma, arrhythmias requiring treatment, hypotension, or death. The following were found to be associated with increased likelihood of major toxicity (p less than 0.05): ingestion of amitriptyline (odds ratio (OR) 2.57), age greater than or equal to 30 years (OR 2.56), heart rate greater than or equal to 120 bpm (OR 2.86), serum tricyclic antidepressant level greater than or equal to 800 ng/mL (OR 5.20), terminal 40 ms QRS axis (T40-ms axis) greater than or equal to 135 degrees (OR 2.73), QRS interval greater than or equal to 100 ms (OR 2.74), QRS axis greater than 90 degrees (OR 3.68), and QTc interval greater than 480 ms (OR 3.89). The mean T40-ms axis on the initial ECG was more rightward in the major toxicity group (174 +/- 84 vs 125 +/- 91 degrees, p = 0.006). We conclude that patients with severe tricyclic antidepressant toxicity tended to have a more rightward T40-ms axis than those with minor toxicity and that the presence of the above parameters was associated with an increased likelihood of severe toxicity.     

Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have increasingly replaced tricyclic antidepressants (TCAs) in the treatment of depression. They appear to be safer in overdose, but there is little information on their spectrum of toxicity in overdose, or relative toxicity of each agent. Objective: To determine the effect of SSRIs in overdose, as a group, and the relative toxicity of five different SSRIs. METHODS: A review of consecutive SSRI poisoning admissions to a single toxicology unit. Outcomes examined were length of stay [LOS], intensive care [ICU] admission rate, coma, seizures, electrocardiographic [ECG] abnormalities, and presence of serotonin syndrome [SS]. Logistic regression was used to model the outcome QTc >440 msec. RESULTS: There were 469 SSRI poisoning admissions analyzed after exclusions. The median LOS for all SSRI overdose admissions was 15.3 h (IQR: 10.5-21.3) and 30 of 469 (6.4%; 95% CI 4.3-9.0%) cases were admitted to ICU. The incidence of seizures was 1.9% and coma was 2.4%. Serotonin syndrome occurred in 14% of overdoses. Comparison of median QTc intervals of the five SSRIs was significantly different (p=0.0002); citalopram (450 IQR: 436-484) was individually different to fluoxetine (p=0.045), fluvoxamine (p=0.022), paroxetine (p=0.0002), and sertraline (p=0.001). The proportion of citalopram overdoses with a QTc >440 msec was 68%, differing significantly from sertraline (adjusted OR: 5.11 95% CI 2.32-11.27). Comparison of median QT intervals of the five SSRIs was statistically different (p=0.026); citalopram (400 IQR: 380-440) was individually different from sertraline (p=0.023). CONCLUSIONS: This study shows SSRIs are relatively safe in overdose despite serotonin syndrome being common. The exception was citalopram, which was significantly associated with QTc prolongation. We believe that cardiac monitoring should be considered in citalopram overdose, particularly with large ingestions and patients with associated cardiac disease.     

An analysis of safety and tolerability data from controlled, comparative studies of quetiapine in patients with schizophrenia, focusing on extrapyramidal symptoms

AIM: This analysis evaluated the tolerability profile of quetiapine using data from all comparative controlled studies in patients with schizophrenia or related disorders in the AstraZeneca clinical trials database, focusing on extrapyramidal symptoms (EPS). METHODS: Adverse event (AE) data from randomised, double-blind, controlled studies in the AstraZeneca clinical trials database were pooled, allowing comparison of quetiapine (mean daily doses 357-496 mg/day) with placebo, haloperidol (10.4 mg/day), risperidone (5.5 mg/day) or chlorpromazine (552 mg/day). Incidence of EPS-related AEs in relation to quetiapine dose was also analysed using a subset of data from fixed-dose studies. RESULTS: Data from 4956 patients were analysed. Quetiapine was well tolerated, and did not increase EPS-related AEs when compared with placebo (9.6 vs. 10.6%, respectively). The incidence of EPS-related AEs with quetiapine was consistent across the dose range (4.2-13.2% vs. 11.1% with placebo). Patients receiving haloperidol, risperidone and chlorpromazine experienced significantly higher levels of EPS-related AEs than those on quetiapine. The most common quetiapine- associated AEs, with significantly higher incidence than placebo, were sedation, somnolence and orthostatic hypotension. CONCLUSION: Quetiapine is generally well tolerated in patients with schizophrenia or related disorders, with placebo-level EPS-related AEs. Quetiapine has a more favourable EPS profile than haloperidol, chlorpromazine or risperidone.     

Fatal overdoses associated with quetiapine

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.