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Acute quetiapine poisoning
The Journal of Emergency Medicine, Vol. 17, No. 6, pp. 995–997, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/99 $–see front matter
PII S0736-4679(99)00128-6
Selected Topics: Toxicology
ACUTE QUETIAPINE POISONING Fredric M. Hustey,
MD
Department of Emergency Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, Reprint Address: Fredric M. Hustey, MD, Department of Emergency Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195
e Abstract—Quetiapine (Seroquel®) is a member of a new class of antipsychotic agents used in the treatment of schizophrenia. Its pharmacologic effect is primarily mediated via antagonistic binding to serotonergic (5HT2) and dopaminergic (D2) receptors. Presented is a case of acute quetiapine overdose in a patient with associated tachycardia, hypotension, prolonged QTc, and rapid progression to coma. Management included activated charcoal, i.v. saline, and intubation for airway protection. The patient’s mental status rapidly improved within several hours of the ingestion, and the prolonged QTc and tachycardia resolved by the second and third days of hospitalization, respectively, without further intervention. This case illustrates the potential for hemodynamic instability and sudden deterioration in level of consciousness, warranting close monitoring and early intubation for airway protection. All patients with acute quetiapine overdose requiring hospitalization should be admitted to an intensive care unit setting. © 1999 Elsevier Science Inc.
through its inhibitory binding of serotonergic (5HT2) and dopaminergic (D2) receptors (1,2). It differs from traditional antipsychotic agents in its high affinity for 5HT2 receptors, while exhibiting a moderate affinity for D2 receptors and low affinity for D1 receptors (1). It also exhibits less antimuscarinic and ␣-1 antagonistic receptor activity. Acute overdose has been reported rarely (six reports in the clinical trial database and two additional published reports) (3–5). We report a case of quetiapine overdose presenting with unresponsiveness, tachycardia, and hypotension. CASE REPORT A 19-year-old male with a history of paranoid schizophrenia and depression was discovered by his parents lethargic and vomiting after ingesting a total of 9,600 mg of quetiapine (58 200-mg tablets). Within 1 h of ingestion, the patient became unresponsive and was found by the responding EMT crew to be hypotensive and tachycardic. He was intubated for airway protection and given intravenous (i.v.) saline for hypotension. The patient arrived at our facility via helicopter approximately 22 h after the ingestion. He was unresponsive and intubated. The vital signs were blood pressure 180/83 mmHg, pulse 138 beats per minute, rectal temperature 36.3° C, and mechanically assisted respirations with an oxygen saturation of 100% on an FiO2 of 100%.
e Keywords—neuroleptics; overdose; quetiapine; Seroquel®; toxicity
INTRODUCTION Quetiapine (Seroquel®) is a new type of antipsychotic agent used in the treatment of schizophrenia. It is classified as a dibenzothiazepine, and is similar to clozapine. Its pharmacological effects are primarily mediated
RECEIVED: 16 October 1998; FINAL ACCEPTED: 24 March 1999
SUBMISSION RECEIVED:
1 March 1999; 995
996
F. M. Hustey
The skin was warm and moist. The pupils were 3 mm, equal, and minimally reactive to light. Cardiopulmonary examination was unremarkable except for tachycardia. The abdomen was soft and nondistended. The extremities were flaccid. The patient had a Glasgow Coma Scale (GCS) score of 3. A comprehensive drug screen was negative, including testing for tricyclic antidepressants (our screen includes amitriptyline, nortriptyline, imipramine, and desipramine), opiates, benzodiazepines, barbiturates, cocaine, amphetamines, PCP, ethanol, and cannabinoids. Arterial blood gas on 100% FiO2 revealed a pH of 7.34, pO2 of 547 mmHg, pCO2 of 42 mmHg, and HCO3⫺ of 23 meq/L. The remainder of the laboratory data in the Emergency Department (ED) was unremarkable (including normal magnesium and calcium levels) except for a mild hypokalemia (3.3 meq/L) and an elevated glucose (137 mg/dL). An electrocardiogram (EKG) revealed a prolonged QTc interval measuring 581 ms. The patient was given 60 grams of activated charcoal and admitted to the medical intensive care unit (MICU). He demonstrated rapid improvement in neurologic status in the MICU. Within 3 h of ED presentation, the patient was localizing pain and had a GCS of 7. By 19 h postpresentation, he was alert and following commands. He was successfully extubated 36 h postpresentation. Serial EKGs demonstrated an interval worsening of the QT prolongation (peaking with a QTc of 710 ms approximately 11 h after presentation). This abnormality was still noted on EKG 19 h after initial presentation but had resolved by 8 h later. The QRS interval remained relatively constant at approximately 100 ms. A mild sinus tachycardia persisted for another 48 h. Blood pressure remained stable. The patient did complain of some intermittent atypical chest pain while in the MICU, the etiology of which was never determined. He was ruled out for mycocardial infarction with EKGs and cardiac enzymes. The patient remained stable and was transferred to the psychiatric service within 72 h of presentation. He subsequently admitted to an isolated quetiapine ingestion totaling 9,600 mg.
DISCUSSION Quetiapine belongs to a new class of antipsychotic agents used in the treatment of schizophrenia. It is an atypical dibenzothiazepine antipsychotic with greater affinity for dopaminergic (D2) and serotonergic (5HT2) receptors. It also has some ␣-one adrenergic and muscarinic receptor antagonistic effects, although these are not believed to be clinically significant. In preliminary studies, it was found to cause fewer extrapyramidal side
effects than traditional antipsychotic agents while proving to be more effective than chlorpromazine and haloperidol in decreasing the positive as well as negative effects of schizophrenia (1,2). There have been very few reports of acute quetiapine overdose in the United States (3–5). Most of these describe symptoms resulting from exaggerations of the drug’s known pharmacological effects (tachycardia, hypotension, sedation). The only reported case similar to ours requiring ICU admission and intubation involved a 26-year-old woman ingesting over 10,000 mg of quetiapine (4). As in our case, the patient had a rapid deterioration in mental status requiring intubation but within 16 h was awake, alert, and subsequently extubated. A sinus tachycardia persisted for about 40 h post-ingestion, but there was no report of QT interval prolongation. In another case, a 21-year-old ingesting 4,700 mg of quetiapine became drowsy and disoriented and developed a persistent tachycardia but did not experience any cardiac conduction abnormalities or hypotension (5). Another estimated overdose of 9,600 mg presented with hypokalemia and first-degree heart block (3). Our case is the only overdose reporting an associated prolongation of the QTc. Treatment is mainly supportive, as there is no specific antidote to quetiapine (3). Many aspects of care are based on speculation, taking into account the pharmacological effects of quetiapine. Hypotension should be aggressively managed with i.v. fluids. Vasoactive drugs such as epinephrine and dopamine may theoretically worsen hypotension (via beta stimulation in the setting of alpha blockade by quetiapine) (3). If pressors are necessary, agents with greater alpha activity (such as norepinephrine) may carry a smaller risk but may also prove less effective in the setting of preexisting quetiapine-induced alpha blockade. Agents that may have an additive effect on QT prolongation (quinidine, procainamide, etc.) probably should be avoided, as they may lower the threshold for cardiac dysrhythmias. Extrapyramidal side effects in acute overdose may respond to anticholinergics (3). Plasma quetiapine levels may be obtained to screen for the presence of the drug and to verify supratherapeutic levels in a questionable or multi-drug ingestion (3,5). Serial levels also may be obtained for patients who exhibit prolonged symptoms. Persistently elevated levels may suggest impaired quetiapine clearance, while levels at or below the therapeutic range may suggest other factors contributing to the patient’s condition. All patients who require hospitalization should be monitored in an ICU setting because of the potential for rapid neurologic deterioration and hemodynamic instability. Although reports of quetiapine overdose are few, ingestions of the related antipsychotic clozapine (which exhibits some similarities to quetiapine in regard to
Acute Quetiapine Poisoning
greater affinity for 5-HT2 receptors and fewer extrapyramidal effects) have been numerous. Clozapine overdose is associated with a high mortality (approximately 12%) (6). Many of the associated symptoms are similar to those encountered in our case, including depressed level of consciousness, tachycardia, and electrocardiographic changes (although dysrhythmias are rarely reported) (7). Aspiration pneumonia is a frequent complication, and treatment is mainly supportive (7).
SUMMARY This case demonstrates the potential for rapid alteration in neurologic and hemodynamic function in patients with acute quetiapine overdose, warranting early intubation for airway protection and the need for intensive care unit monitoring in all patients requiring hospitalization. There are a limited number of reports of quetiapine overdose, and more clinical experience is needed to further assist in
997
the understanding and management of the overdose patient.
REFERENCES 1. Anonymous. Seroquel: A putative atypical antipsychotic drug with serotonin- and dopamine-receptor antagonist properties. Preclinical and early clinical trials in schizophrenia. J Clin Psychiatry 1995;56:438 – 45. 2. Borison RL, Arvanitis LA, Miller BG. ICI 204,636, an atypical antipsychotic. Efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. J Clin Psychopharmacol 1996;16:158 – 69. 3. Seroquel (Quetiapine Fumarate) tablets. Professional Information Brochure. Manufactured by: Zeneca Pharmaceuticals. 4. Harmon TJ, Benitez JG, Krenzelok EP, Cortes BE. Loss of consciousness from acute quetiapine overdosage. J Toxicol Clin Toxicol 1998;36:599 – 602. 5. Nudelman E, Vinuela L, Cohen C. Safety of overdose of quetiapine: a case report. J Clin Psychiatry 1998;59:433. 6. Piccini G, Ceroni P, Marchesi C, Maggini C, Maestri G. Acute clozapine overdosage (letter). Br J Psychiatry 1997;170:290. 7. LeBlaye I, Donatini B, Hall M, et al. Acute overdosage with clozapine: a review of the available clinical experience. Pharm Med 1992;6(3):169 –78.
PII S0736-4679(99)00128-6
Selected Topics: Toxicology
ACUTE QUETIAPINE POISONING Fredric M. Hustey,
MD
Department of Emergency Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, Reprint Address: Fredric M. Hustey, MD, Department of Emergency Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195
e Abstract—Quetiapine (Seroquel®) is a member of a new class of antipsychotic agents used in the treatment of schizophrenia. Its pharmacologic effect is primarily mediated via antagonistic binding to serotonergic (5HT2) and dopaminergic (D2) receptors. Presented is a case of acute quetiapine overdose in a patient with associated tachycardia, hypotension, prolonged QTc, and rapid progression to coma. Management included activated charcoal, i.v. saline, and intubation for airway protection. The patient’s mental status rapidly improved within several hours of the ingestion, and the prolonged QTc and tachycardia resolved by the second and third days of hospitalization, respectively, without further intervention. This case illustrates the potential for hemodynamic instability and sudden deterioration in level of consciousness, warranting close monitoring and early intubation for airway protection. All patients with acute quetiapine overdose requiring hospitalization should be admitted to an intensive care unit setting. © 1999 Elsevier Science Inc.
through its inhibitory binding of serotonergic (5HT2) and dopaminergic (D2) receptors (1,2). It differs from traditional antipsychotic agents in its high affinity for 5HT2 receptors, while exhibiting a moderate affinity for D2 receptors and low affinity for D1 receptors (1). It also exhibits less antimuscarinic and ␣-1 antagonistic receptor activity. Acute overdose has been reported rarely (six reports in the clinical trial database and two additional published reports) (3–5). We report a case of quetiapine overdose presenting with unresponsiveness, tachycardia, and hypotension. CASE REPORT A 19-year-old male with a history of paranoid schizophrenia and depression was discovered by his parents lethargic and vomiting after ingesting a total of 9,600 mg of quetiapine (58 200-mg tablets). Within 1 h of ingestion, the patient became unresponsive and was found by the responding EMT crew to be hypotensive and tachycardic. He was intubated for airway protection and given intravenous (i.v.) saline for hypotension. The patient arrived at our facility via helicopter approximately 22 h after the ingestion. He was unresponsive and intubated. The vital signs were blood pressure 180/83 mmHg, pulse 138 beats per minute, rectal temperature 36.3° C, and mechanically assisted respirations with an oxygen saturation of 100% on an FiO2 of 100%.
e Keywords—neuroleptics; overdose; quetiapine; Seroquel®; toxicity
INTRODUCTION Quetiapine (Seroquel®) is a new type of antipsychotic agent used in the treatment of schizophrenia. It is classified as a dibenzothiazepine, and is similar to clozapine. Its pharmacological effects are primarily mediated
RECEIVED: 16 October 1998; FINAL ACCEPTED: 24 March 1999
SUBMISSION RECEIVED:
1 March 1999; 995
996
F. M. Hustey
The skin was warm and moist. The pupils were 3 mm, equal, and minimally reactive to light. Cardiopulmonary examination was unremarkable except for tachycardia. The abdomen was soft and nondistended. The extremities were flaccid. The patient had a Glasgow Coma Scale (GCS) score of 3. A comprehensive drug screen was negative, including testing for tricyclic antidepressants (our screen includes amitriptyline, nortriptyline, imipramine, and desipramine), opiates, benzodiazepines, barbiturates, cocaine, amphetamines, PCP, ethanol, and cannabinoids. Arterial blood gas on 100% FiO2 revealed a pH of 7.34, pO2 of 547 mmHg, pCO2 of 42 mmHg, and HCO3⫺ of 23 meq/L. The remainder of the laboratory data in the Emergency Department (ED) was unremarkable (including normal magnesium and calcium levels) except for a mild hypokalemia (3.3 meq/L) and an elevated glucose (137 mg/dL). An electrocardiogram (EKG) revealed a prolonged QTc interval measuring 581 ms. The patient was given 60 grams of activated charcoal and admitted to the medical intensive care unit (MICU). He demonstrated rapid improvement in neurologic status in the MICU. Within 3 h of ED presentation, the patient was localizing pain and had a GCS of 7. By 19 h postpresentation, he was alert and following commands. He was successfully extubated 36 h postpresentation. Serial EKGs demonstrated an interval worsening of the QT prolongation (peaking with a QTc of 710 ms approximately 11 h after presentation). This abnormality was still noted on EKG 19 h after initial presentation but had resolved by 8 h later. The QRS interval remained relatively constant at approximately 100 ms. A mild sinus tachycardia persisted for another 48 h. Blood pressure remained stable. The patient did complain of some intermittent atypical chest pain while in the MICU, the etiology of which was never determined. He was ruled out for mycocardial infarction with EKGs and cardiac enzymes. The patient remained stable and was transferred to the psychiatric service within 72 h of presentation. He subsequently admitted to an isolated quetiapine ingestion totaling 9,600 mg.
DISCUSSION Quetiapine belongs to a new class of antipsychotic agents used in the treatment of schizophrenia. It is an atypical dibenzothiazepine antipsychotic with greater affinity for dopaminergic (D2) and serotonergic (5HT2) receptors. It also has some ␣-one adrenergic and muscarinic receptor antagonistic effects, although these are not believed to be clinically significant. In preliminary studies, it was found to cause fewer extrapyramidal side
effects than traditional antipsychotic agents while proving to be more effective than chlorpromazine and haloperidol in decreasing the positive as well as negative effects of schizophrenia (1,2). There have been very few reports of acute quetiapine overdose in the United States (3–5). Most of these describe symptoms resulting from exaggerations of the drug’s known pharmacological effects (tachycardia, hypotension, sedation). The only reported case similar to ours requiring ICU admission and intubation involved a 26-year-old woman ingesting over 10,000 mg of quetiapine (4). As in our case, the patient had a rapid deterioration in mental status requiring intubation but within 16 h was awake, alert, and subsequently extubated. A sinus tachycardia persisted for about 40 h post-ingestion, but there was no report of QT interval prolongation. In another case, a 21-year-old ingesting 4,700 mg of quetiapine became drowsy and disoriented and developed a persistent tachycardia but did not experience any cardiac conduction abnormalities or hypotension (5). Another estimated overdose of 9,600 mg presented with hypokalemia and first-degree heart block (3). Our case is the only overdose reporting an associated prolongation of the QTc. Treatment is mainly supportive, as there is no specific antidote to quetiapine (3). Many aspects of care are based on speculation, taking into account the pharmacological effects of quetiapine. Hypotension should be aggressively managed with i.v. fluids. Vasoactive drugs such as epinephrine and dopamine may theoretically worsen hypotension (via beta stimulation in the setting of alpha blockade by quetiapine) (3). If pressors are necessary, agents with greater alpha activity (such as norepinephrine) may carry a smaller risk but may also prove less effective in the setting of preexisting quetiapine-induced alpha blockade. Agents that may have an additive effect on QT prolongation (quinidine, procainamide, etc.) probably should be avoided, as they may lower the threshold for cardiac dysrhythmias. Extrapyramidal side effects in acute overdose may respond to anticholinergics (3). Plasma quetiapine levels may be obtained to screen for the presence of the drug and to verify supratherapeutic levels in a questionable or multi-drug ingestion (3,5). Serial levels also may be obtained for patients who exhibit prolonged symptoms. Persistently elevated levels may suggest impaired quetiapine clearance, while levels at or below the therapeutic range may suggest other factors contributing to the patient’s condition. All patients who require hospitalization should be monitored in an ICU setting because of the potential for rapid neurologic deterioration and hemodynamic instability. Although reports of quetiapine overdose are few, ingestions of the related antipsychotic clozapine (which exhibits some similarities to quetiapine in regard to
Acute Quetiapine Poisoning
greater affinity for 5-HT2 receptors and fewer extrapyramidal effects) have been numerous. Clozapine overdose is associated with a high mortality (approximately 12%) (6). Many of the associated symptoms are similar to those encountered in our case, including depressed level of consciousness, tachycardia, and electrocardiographic changes (although dysrhythmias are rarely reported) (7). Aspiration pneumonia is a frequent complication, and treatment is mainly supportive (7).
SUMMARY This case demonstrates the potential for rapid alteration in neurologic and hemodynamic function in patients with acute quetiapine overdose, warranting early intubation for airway protection and the need for intensive care unit monitoring in all patients requiring hospitalization. There are a limited number of reports of quetiapine overdose, and more clinical experience is needed to further assist in
997
the understanding and management of the overdose patient.
REFERENCES 1. Anonymous. Seroquel: A putative atypical antipsychotic drug with serotonin- and dopamine-receptor antagonist properties. Preclinical and early clinical trials in schizophrenia. J Clin Psychiatry 1995;56:438 – 45. 2. Borison RL, Arvanitis LA, Miller BG. ICI 204,636, an atypical antipsychotic. Efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. J Clin Psychopharmacol 1996;16:158 – 69. 3. Seroquel (Quetiapine Fumarate) tablets. Professional Information Brochure. Manufactured by: Zeneca Pharmaceuticals. 4. Harmon TJ, Benitez JG, Krenzelok EP, Cortes BE. Loss of consciousness from acute quetiapine overdosage. J Toxicol Clin Toxicol 1998;36:599 – 602. 5. Nudelman E, Vinuela L, Cohen C. Safety of overdose of quetiapine: a case report. J Clin Psychiatry 1998;59:433. 6. Piccini G, Ceroni P, Marchesi C, Maggini C, Maestri G. Acute clozapine overdosage (letter). Br J Psychiatry 1997;170:290. 7. LeBlaye I, Donatini B, Hall M, et al. Acute overdosage with clozapine: a review of the available clinical experience. Pharm Med 1992;6(3):169 –78.