Abnormal blood concentration changes in a 71-year-old female who survived a 10,000mg overdose of clozapine: a case report.

BACKGROUND: Clozapine is a highly effective second-generation antipsychotic with few extrapyramidal reactions, making it a preferred choice among clinicians. However, instances of acute clozapine poisoning resulting from suicide attempts and misuse have been reported. Through our review of existing literature, we identified that we believe to be the highest recorded overdose of clozapine in elderly patients, resulting in a nonfatal outcome. CASE PRESENTATION: The case report involves a 71-year-old female with a history of depression who ingested a dose of 10,000 mg of clozapine. Approximately 6 h after the overdose, the clozapine level was 5,200 µg/L, significantly surpassing the recommended therapeutic concentration range of 350-600 µg/L. After gastric lavage and hemoperfusion, the blood level dropped to 1847.11 µg/L. Notably, during therapeutic drugs monitoring (TDM), we found a perplexing spike in the patient's blood level to 5554.15 µg/L after the second hemoperfusion. CONCLUSION: In this case we mainly focused on the abnormal fluctuations in the concentration of clozapine. We conducted a comprehensive analysis of potential factors contributing to this abnormal phenomenon in terms of the patient's age, clinical symptoms, various laboratory test indexes, and the pharmacokinetics of clozapine. Our findings underscore the importance of timely TDM and the precision of results in managing elderly patients experiencing high-dose clozapine poisoning.

Antipsychotic-Related Fatal Poisoning, England and Wales, 1993-2019: The Impact of Second-Generation Antipsychotics.

BACKGROUND: Deaths from antipsychotic (AP) poisoning have increased in England and Wales despite restriction of the use of thioridazine in 2000. METHODS: We analyzed data from the Office for National Statistics drug-related death database, England and Wales, 1993-2019, to investigate fatal AP poisoning. RESULTS: There were 2286 deaths (62% male patients). Annual numbers of intentional AP-related fatal poisonings (suicides) were relatively stable (1993, 35; 2019, 44; median, 44; range, 30-60). Intentional overdose deaths involving clozapine (96 male, 25 female) increased from 1 in 1994 to 5 in 2003 and have since remained relatively constant (median, 6; range, 3-10 per annum). Unintentional second-generation AP-related fatal poisonings have increased steadily since 1998, featuring in 828 (74%) of all unintentional, AP-related fatal poisonings in the period studied (2019, 89%). There were 181 unintentional clozapine-related deaths, (107 [59%] alone without other drugs ± alcohol) as compared with 291 quetiapine-related deaths (86 [30%] alone without other drugs ± alcohol) and 314 unintentional olanzapine-related deaths (77 [25%] alone without other drugs ± alcohol). Some 75% of all unintentional clozapine- and olanzapine-related deaths were of male patients (78% and 73%, respectively) as compared with 58% of unintentional quetiapine-related fatal poisonings. Clozapine now features prominently in intentional and in unintentional AP-related fatal poisoning in England and Wales. Deaths of male patients predominate in both categories. There were also 77 and 86 deaths attributed to unintentional poisoning with olanzapine and with quetiapine, respectively, in the absence of other drugs. CONCLUSIONS: More effort is needed to prevent unintentional deaths not only from clozapine but also from olanzapine and quetiapine.

Intravenous lipid emulsion as an adjuvant therapy of acute clozapine poisoning.

INTRODUCTION: Clozapine is a frequently prescribed atypical antipsychotic drug. Various case reports documented the successful recovery of acute antipsychotics toxicity in association with the administration of intralipid emulsion (ILE). AIM: This study aimed to assess the adjuvant therapeutic role of SMOF Lipid administration on the outcomes of acute clozapine poisoning. METHODS: Forty patients with acute clozapine poisoning were randomly allocated into two equal groups. The control group received the standard supportive treatment only, whereas the intervention group received the standard supportive treatment plus SMOF Lipid 20% infusion. All patients were subjected to history taking, full clinical examination, and laboratory investigations. The study outcomes were evaluated. RESULTS: The mean Glasgow Coma Scale (GCS) at 6 hours (13.1 ± 2.3 vs 9.2 ± 2, p < 0.001) and 12 hours (14.3 ± 1.5 vs 9.6 ± 2, p < 0.001) after admission was significantly higher in the intervention group compared to the control group. The intervention group showed a significantly lower frequency of prolonged QTc interval 12 hours after admission (p = 0.003), as well as a significantly shorter hospital stay (p < 0.001). CONCLUSIONS: SMOF Lipid infusion seemed to have improved GCS, the prolonged QTc interval, and shortened the length of hospital stay. Furthermore, there were no adverse effects related to its administration.

Sulpiride intoxication: Case report of a rare intoxication.

Intoxications with sulpiride, an antipsychotic, are rare, and only limited literature is available. We describe a successful treatment of a sulpiride intoxication. A 67-year-old female, with a history of intentional suicide attempt, was admitted to the emergency department (ED) because of a suspected out-of-hospital cardiac arrest. At presentation, she was haemodynamically unstable, with a Glasgow Coma Scale of 3 and slight prolongation of QTc time. History taken from her husband raised suspicion of a suicide attempt with medication. Consultation of the on-call pharmacist and performance of a toxicology screening accelerated the diagnosis of a sulpiride intoxication. The patient was intubated because of respiratory insufficiency, admitted to the Intensive Care Unit (ICU) and treated with activated charcoal, laxatives and sodium bicarbonate. The following day, she was extubated with stable haemodynamics and a normalized ECG. Treatment of sulpiride intoxications is mainly symptomatic and consists of supportive care. An important note is the avoidance of antiarrhythmic drugs, except for lidocaine, epinephrine and dopamine, as they might worsen arrhythmia and hypotension.

Vasopressor therapy in atypical antipsychotic overdose.

Hypotension is a common presentation following an overdose of quetiapine. Adrenaline is often used as the vasopressor of choice for hypotension not responding to intravenous fluids. We present a case of quetiapine overdose with hypotension unresponsive to high-dose adrenaline. The patient was commenced on noradrenaline and made a full recovery. We highlight learning points about vasopressor therapy for atypical antipsychotic overdose. Quetiapine-induced hypotension is thought to be mediated by α1-receptor antagonism. Adrenaline is unlikely to improve blood pressure, as it is an agonist at both α- and ß-receptors. Alpha-2- and ß2-agonism can reduce sympathetic outflow and cause vasodilation, respectively, further exacerbating the hypotension. Noradrenaline is the preferred vasopressor of choice for hypotension caused by quetiapine overdose, as it has less affinity for α2- and ß2-receptors, but maintains α1-receptor agonism. Drugs with a similar mechanism of inducing hypotension should also be treated with noradrenaline as the vasopressor of choice.

The systemic inflammatory response syndrome in acute antipsychotic poisoning.

The purpose of this study was to investigate the mutual effect of systemic inflammatory response syndrome (SIRS) accompanied with fibrinolysis, endotoxemia, and coagulation in severe cases of antipsychotic poisoning. A total of 199 patients were examined, of which 71 were men and 128 were women. The age of the patients was from 22 to 63 years, (45.3 ± 6.1 years on average). According to the results of the course of therapy, the patients were divided into two groups. In the blood plasma, the content of C-reactive protein, fibrinogen and its proteolysis products (oligopeptides, D-dimers), interleukin-6 were determined. In the first 1 to 3 days, in group 1, the level of interleukin-6 decreased and approached the normal level (P ≤ .05). The opposite trend continued throughout the observation of patients from group 2-their levels of interleukin-6 increased day by day (P ≤ .05). The concentration of D-dimer already in 1 day after admission to intensive care in patients from group 2 exceeded the norm by 14 times (P ≤ .05). The level of D-dimer correlated with the level of oligopeptides in blood plasma upon admission, as well as for 3 and 5 days after admission to intensive care: 0.36, 0.76 at P ≤ .05, 0.94 at P ≤ .01, respectively. Similar correlations were obtained for the content of oligopeptides in urine and the level of D-dimer: 0.55, 0.85 at P ≤ .05, 0.93 at P ≤ .01. In this regard, the most pronounced correlation is that between the SIRS score, plasma D-dimer level, and the plasma level of the D-dimer derivatives, oligopeptides.

Non-Opioid Substances Acute Poisonings with Suicidal Intent in Patients with Opioid Use Disorder.

INTRODUCTION: Several epidemiological studies have evaluated the role of illicit drug use in suicide behaviour. AIM: To assess patients with opioid use disorder and suicidal intent related to behavior, severity of acute poisoning and the most commonly used non-opioid substances. MATERIALS AND METHODS: This cross sectional study included 67 patients diagnosed with opioid use disorder. The study was conducted at the University Clinic of Toxicology in Skopje over a 5-year period (2013-2017). The following variables were examined: gender, age, duration and route of opioid administration, duration of hospitalization, and types of substances used in acute poisoning. Assessment of patients' behavior and severity of poisoning was made by using the Suicide Behaviours Questionnaire-Revised and the Poison severity score. RESULTS: The majority of patients were male (88.1%). The mean age of patients was 30±6.1 years. The average duration of opioid use disorder was 8.5±3.9. A single poisoning was found in 62.7%, double poisoning in 25.4%, and triple poisoning in 11.9% of participants. Benzodiazepines were most commonly used by the patients (55.2%). The largest number of patients (32.8%) had minor Poison severity score (PSS), and only 17.9% had severe PSS. None of the patients had a fatal suicide attempt. 86.6% of patients had a score of ≥7 indicating a high risk of repeat suicide attempts. CONCLUSION: Benzodiazepines were most commonly used as a single or combined substance in patients with opioid use disorder. PSS indicated that most of the participants were with minor PSS and with high risk of a repeat suicide attempt.

Characterization of intentional lurasidone ingestions using the United States National Poison Data System.

Introduction: The ziprasidone analogue lurasidone is approved for the treatment of schizophrenia and bipolar disorder for adults and children older than 10 years. Small studies and case reports suggest lurasidone overdose is not generally associated with major adverse effects, but no large sample has been published.Objective: To describe intentional lurasidone overdoses reported to poison centers.Methods: Retrospective analysis of single-substance intentional lurasidone ingestions from the National Poison Data System (NPDS) from 2011 to 2018.Results: There were 1753 single-substance intentional overdoses. Average age was 28.6 years (SD = 13.3 years) and 1199 (68.4%) of patients were female. Most cases (86.6%) were coded as suspected suicide. Regarding final management site, 1143 (65.2%) were discharged or admitted to psychiatric facilities; 328 (18.8%) were admitted, half of whom were admitted to critical care units (CCUs). Major effect was coded in 12 (0.7%), moderate effect in 259 (14.8%), minor effect in 531 (30%), and no effect in 614 (35%). There were no deaths. For cases for which dose information was available, there was not a statistically significant difference between median doses when analyzed by clinical effect. Most common adverse effects were drowsiness (449, 25.6%), tachycardia (254, 14.5%), vomiting (121, 6.9%), and hypertension (115, 6.6%). Most cases had either no therapy reported, or therapy was recommended by the poison center but confirmed not to have been administered (1010, 57.6%). Of the 164 patients admitted to CCUs, 80 (48.8%) received either no therapy or intravenous fluids alone.Discussion: These data suggest major effects are uncommon from lurasidone overdose. Despite a high rate of admission to CCUs, a substantial proportion received no critical therapies.Conclusions: This report demonstrates intentional lurasidone overdoses reported to poison centers generally have a favorable clinical course.

Hospital-treated deliberate self-poisoning in the older adult: Identifying specific clinical assessment needs.

BACKGROUND: Hospital-treated deliberate self-poisoning is common, with a median patient age of around 33 years. Clinicians are less familiar with assessing older adults with self-poisoning and little is known about their specific clinical requirements. OBJECTIVE: To identify clinically important factors in the older-age population by comparing older adults (65+ years) with middle-aged adults (45-64 years) during an index episode of hospital-treated deliberate self-poisoning. METHODS: A prospective, longitudinal, cohort study of people presenting to a regional referral centre for deliberate self-poisoning (Calvary Mater Newcastle, Australia) over a 10-year period (2003-2013). We compared older-aged adults with middle-aged adults on demographic, toxicological and psychiatric variables and modelled independent predictors of referral for psychiatric hospitalisation on discharge with logistic regression. RESULTS: There were (n = 157) older-aged and (n = 925) middle-aged adults. The older-aged group was similar to the middle-aged group in several ways: proportion living alone, reporting suicidal ideation/planning, prescribed antidepressant and antipsychotic drugs, and with a psychiatric diagnosis. However, the older-aged group were also different in several ways: greater proportion with cognitive impairment, higher medical morbidity, longer length of stay, and greater prescription and ingestion of benzodiazepines in the deliberate self-poisoning event. Older age was not a predictor of referral for psychiatric hospitalisation in the multivariate model. CONCLUSION: Older-aged patients treated for deliberate self-poisoning have a range of clinical needs including ones that are both similar to and different from middle-aged patients. Individual clinical assessment to identify these needs should be followed by targeted interventions, including reduced exposure to benzodiazepines.

When clozapine appears at a dance event .

Objectives: The content of substances sold and consumed as party drugs is often unknown. They may contain inactive, contaminated or unexpected ingredients, and the dosage of the active components may vary considerably. Obviously, these phenomena increase the chances of a wrong or delayed therapy. To illustrate this point, we report 3 cases of clozapine intoxication at a dance event where most likely clozapine tablets were sold as party drugs.Methods: The three cases were part of a prospective toxicology study at a nocturnal indoor dance event.Results: One patient had to be intubated after obstructive breathing with desaturation and bradycardia, while the 2 other patients presented with syncope and altered mental status. All patients recovered after 20 minutes to 8 hours. Systematic toxicological analysis of the blood samples revealed the presence of clozapine (73-244 ng/ml) and its metabolite norclozapine (9-59 ng/ml). A pill, found in a pocket of one patient, was identified as Leponex® 100 mg (clozapine). This neuroleptic drug is mainly prescribed for treatment-resistant schizophrenia. In clozapine-naive subjects, orthostatic hypotension, bradycardia and syncope have been reported with a single 25 mg oral dose. Serum clozapine concentrations of the 3 cases were below the defined therapeutic range (350-600ng/ml) and the clozapine:norclozapine ratios were suggestive for recent drug intake.Conclusion: Routine drug screening may be unable to detect the toxic agent(s) involved. Whenever unusual symptoms are observed in an intoxicated patient, blood and urine samples should be sent to a reference toxicology laboratory.

[Analysis of risk factors, etiology and treatment standard of lithium poisoning]. / Analyse zu Risikofaktoren, Ätiologie und Behandlungsstandard der Lithiumintoxikation.

Despite unlimited access to therapeutic drug monitoring lithium poisoning is still a common and potentially life-threatening but in most cases preventable complication of lithium treatment; however, it is still considered to be the gold standard in the treatment of affective disorders. The necessity of drug monitoring and potential lithium toxicity substantiate the skepticism of many therapists with respect to this often very effective treatment. This therefore limits the use of lithium although the unique therapeutic effects and high efficiency are well known. This retrospective data analysis of risk factors and etiology of lithium poisoning cases identified 58 cases of lithium poisoning, which were treated internally in this hospital between 2010 and 2014. Of the patients 67.2% were female and the majority were classified as chronic poisoning (66.1%). The most relevant patient-related risk factor seemed to be insufficient self-management as 26% of cases of lithium poisoning occurred during febrile infections or exsiccosis. Regarding practitioner-related risk factors, an insufficient consideration of drug interactions, insufficient therapeutic drug monitoring after dose increase and a paucity of experience and knowledge concerning lithium treatment were most relevant. This study illustrates the most important risk factors for lithium poisoning and their frequencies and contributes to raise awareness for this highly relevant topic. These data can help to prevent further cases of lithium poisoning. Furthermore, the results enable a comparison between the actual treatment reality and currently available evidence for the treatment of lithium poisoning.

Drug-Induced Extrapyramidal Symptoms at the Pediatric Emergency Department.

OBJECTIVES: Extrapyramidal symptoms (EPS) induced by pharmacologic agents can cause patient discomfort and lead to emergency department visits. Analyzing these cases at a pediatric emergency department may help to elucidate the characteristic features of extrapyramidal syndrome in children. METHODS: This retrospective study was conducted at Chang Gung Memorial Hospital in Taiwan. Pediatric patients with drug-induced extrapyramidal syndrome seeking treatment at our emergency department from January 2001 to December 2010 were enrolled. The patients' clinical features, drug history, demographic data, and treatment data were collected and analyzed. RESULTS: One hundred nineteen patients (61 females, 58 males) were enrolled. Ninety-six patients could provide their drug history; all of whom took dopamine antagonists and 90% of whom took dopamine antagonists as antiemetic agents, with only 9 patients taking them for antipsychotic purposes. Metoclopramide syrup overdose was the main cause of extrapyramidal syndrome in patients under 2 years old. The average emergency room stay of the patients who could provide their drug history was shorter than that of those who could not. CONCLUSIONS: It is not uncommon for patients with drug-induced EPS to present to a pediatric emergency room owing to the use of dopamine antagonists as antiemetic agents. Clinical symptoms with a clear drug history are helpful for the diagnosis and management. Emphasizing the correct usage of liquid medications will reduce the risk of EPS.

Delayed-Onset Toxicity in an Adolescent Case Following Attempted Suicide with an Overdose of Paliperidone Intake.

Paliperidone is a relatively novel atypical antipsychotic drug that is currently used to treat schizophrenia in adolescents and adults. The drug was generated by combining the active metabolite of risperidone, 9-hydroxyrisperidone, with osmotic controlled-release oral administration system (OROS) technology. Due to its specific design, the drug has been identified as a different form, albeit an active metabolite of risperidone. Such distinction mainly manifests itself during pharmacokinetic processes, because paliperidone is not affected by CYP2D6 metabolism. On the other hand, this drug is regularly released for a period of 24 hours. Even though it is possible to reach relevant literature on the efficacy and safety of paliperidone use in detail, limited data regarding its toxicity exists. A review of the literature in that sense, has revealed a scarce number of case reports and a retrospective study existing. Bearing in mind the specific form and design of the drug, we have hypothesized its toxicity might cause diverse clinical presentations, in the face of overdose or poisoning. This might in turn, prompt us to switch our usual evaluation and intervention practices. With this case report, we have aimed to discuss delayed onset toxicity with paliperidone overdose in an adolescent case, due to a suicide attempt with excessive intake of the medication.

Childhood Drug and Non-Drug Poisoning in Nigeria: An Economic Appraisal.

BACKGROUND: The dearth of information on the economic cost of childhood poisoning in sub-Saharan Africa necessitated this study. OBJECTIVE: This study has investigated the prevalence of childhood drug and non-drug poisoning, treatment modalities and economic costs in Nigeria. METHOD: A retrospective study of childhood drug and non-drug poisoning cases from January 2007 to June 2014 in the University of Port Harcourt Teaching Hospital (UPTH), Port Harcourt, Nigeria was carried out. Medical records were analysed for demographic and aetiological characteristics of poisoned children (0-14 years of age), as well as fiscal impact of poisoning cases. FINDINGS: Of the 100 poisoned patients, 46% were male and 54% female, with female/male ratio of 1.17:1. Most of the children were under five years of age. Paracetamol, amitriptyline, chlorpromazine, ferrous sulphate, kerosene, organophosphates, carbon monoxide, snake bite, alcohol and rodenticides were involved in the poisoning. The average cost of poison management per patient was about $168, which is high given the economic status of Nigeria. CONCLUSION: Childhood poisoning is still a significant cause of morbidity among children in Nigeria and accounts for an appreciable amount of health spending, therefore preventive strategies should be considered.

Quetiapine Poisoning and Factors Influencing Severity.

PURPOSE/BACKGROUND: Quetiapine is a relatively new atypical antipsychotic with fewer adverse effects. It is increasingly prescribed to patients. The purpose of this study was to describe the cases of poisoning observed at the western France Poison Control Centre and identify potential risk factors that increase the severity of the cases. METHODS: This was a retrospective study of self-poisoning with quetiapine as reported by the western France Poison Control Centre between 2007 and 2017. RESULTS: There were 372 cases of quetiapine poisoning. Circumstances are known in 367 of 372 cases. There were 75 cases of null severity (grade 0), 133 cases of mild severity (grade 1), 85 cases of moderate severity (grade 2), and 79 cases of high severity (grade 3). Five deaths were listed in this series. The most commonly observed symptoms were neurological and cardiovascular in nature (drowsiness, coma, tachycardia, hypotension). Of these cases, 79.8% included voluntary ingestions. Among 302 cases with coagents, the most common coagents were benzodiazepines (56%), other psychotropic drugs (41%), and antidepressants (37%). An evaluated ingested dose 1500 mg or greater and 2 or more coagents increase the risk of severe poisoning. In particular, concomitant ingestion of benzodiazepines and antidepressants with quetiapine was associated with high severity (odds ratio, 2.478 [confidence interval, 1.3-4.723]; odds ratio, 1.820 [confidence interval, 1.010-3.316]). CONCLUSIONS: Quetiapine may lead to severe poisoning for which there is currently no specific treatment. Patients and practitioners should be aware of this when quetiapine is prescribed, particularly when used in combination with other medications, and in order to deal with cases of poisoning.

Complete atrioventricular block associated with clozapine intoxication: case report.

Türe M, Bilici M, Akin A, Demir F, Balik H, Darakçi SM. Complete atrioventricular block associated with clozapine intoxication: case report. Turk J Pediatr 2019; 61: 618-621. Clozapine is one of the atypical anti-psychotic drugs used in the treatment of resistant schizophrenia. Although cardiac side-effects are rare, it has been reported that there may be development of myocarditis, dilated cardiomyopathy, postural orthostatic hypotension and prolonged QT duration. Complete atrioventricular (AV) block is characterized by the inability to transmit all of the atrial signal to the ventricles. Causes may be congenital, idiopathic or acquired which are associated with surgery, infection, or muscle disease. AV block is extremely serious and permanent pacemaker insertion is usually necessary for all patients. Complete AV block may develop due to clozapine intoxication through increase in vagal tonus, sinoatrial node (SN) and the inhibition of atrioventricular node signalling. The case presented here is of a 15-year old female patient who developed AV total cardiac block associated with the taking of clozapine in a suicide attempt.

Extended-release quetiapine overdose is associated with delayed onset of toxicity compared to immediate-release quetiapine overdose.

OBJECTIVES: There are currently no studies comparing toxicity after extended-release (XR) and immediate-release (IR) quetiapine overdose. To compare the time course of toxicity of XR and IR quetiapine overdose. METHODS: Retrospective analysis of toxicology unit consultations from July 2013 to April 2016. Information extracted included demographics, type of ingestion (IR, XR, mixed formulation, dose, tablet count, time to presentation, sedative co-ingestants), lowest Glasgow coma score (GCS), time to lowest GCS, fastest pulse, lowest systolic blood pressure, and time to recovery from sedation. RESULTS: There were 256 presentations in 210 patients. Females 86% (n = 181), median age 30.5 years (IQR 23-43). Median quetiapine dose for the whole cohort was 2 g (IQR 1-5). Sedating co-ingestants were seen in 61% of presentations. Comparison of IR (n = 43) and XR quetiapine (n = 23) ingestions without sedating co-ingestants revealed a larger median ingested dose for XR formulation: 5.7 g versus 1.75 g (P = 0.004) and larger median tablet strength (XR 200 mg vs IR 100 mg, P < 0.001). Median time to lowest GCS: XR 7 h (IQR 4.9-11) versus IR 3.8 h (IQR 2.4-5.7), P < 0.001. Median time to peak pulse: XR 9 h (IQR 3-12) versus IR 2.5 h (IQR 1.5-5), P = 0.01. Median time to recovery from sedation: XR quetiapine 20 h (IQR 12-39) versus 12 h (IQR 5.5-22), P < 0.05. Median duration of intubation: XR 47 h versus 17 h for IR, P = 0.04). CONCLUSION: XR quetiapine overdoses without sedating co-ingestants were associated with a doubling of time to peak sedation and pulse, and had longer recovery from sedation. The absence of sedation or tachycardia 12 h post-overdose of XR quetiapine seems a reasonable timeframe to rule out significant poisoning.