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1.
BMC Psychiatry ; 24(1): 123, 2024 Feb 14.
Article in English | MEDLINE | ID: mdl-38355481

ABSTRACT

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.


Subject(s)
Antipsychotic Agents , Clozapine , Drug Overdose , Aged , Female , Humans , Antipsychotic Agents/poisoning , Clozapine/poisoning , Drug Monitoring/methods , Suicide, Attempted
2.
J Clin Psychopharmacol ; 41(6): 650-657, 2021.
Article in English | MEDLINE | ID: mdl-34668874

ABSTRACT

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.


Subject(s)
Antipsychotic Agents/poisoning , Clozapine/poisoning , Drug Overdose/mortality , Drug-Related Side Effects and Adverse Reactions/mortality , Olanzapine/poisoning , Poisoning/mortality , Adult , England/epidemiology , Female , Humans , Male , Middle Aged , Wales/epidemiology
3.
Hum Exp Toxicol ; 40(7): 1053-1063, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33401984

ABSTRACT

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.


Subject(s)
Antidotes/therapeutic use , Antipsychotic Agents/poisoning , Clozapine/poisoning , Fat Emulsions, Intravenous/therapeutic use , Fish Oils/therapeutic use , Olive Oil/therapeutic use , Poisoning/drug therapy , Soybean Oil/therapeutic use , Triglycerides/therapeutic use , Adolescent , Adult , Child , Child, Preschool , Combined Modality Therapy , Egypt , Female , Humans , Male , Treatment Outcome , Young Adult
5.
Acta Clin Belg ; 75(6): 416-420, 2020 Dec.
Article in English | MEDLINE | ID: mdl-31199195

ABSTRACT

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.


Subject(s)
Antipsychotic Agents/poisoning , Bradycardia/chemically induced , Clozapine/poisoning , Hypoxia/chemically induced , Illicit Drugs , Syncope/chemically induced , Clozapine/analogs & derivatives , Clozapine/blood , Electrocardiography , Female , Humans , Male , Young Adult
6.
Turk J Pediatr ; 61(4): 618-621, 2019.
Article in English | MEDLINE | ID: mdl-31990485

ABSTRACT

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.


Subject(s)
Atrioventricular Block/chemically induced , Atrioventricular Node/physiopathology , Clozapine/poisoning , Electrocardiography/drug effects , Adolescent , Antipsychotic Agents/poisoning , Atrioventricular Block/physiopathology , Atrioventricular Block/therapy , Atrioventricular Node/drug effects , Female , Humans , Pacemaker, Artificial , Suicide, Attempted
7.
Anal Chim Acta ; 1014: 64-70, 2018 Jul 19.
Article in English | MEDLINE | ID: mdl-29523253

ABSTRACT

Antipsychotics are the drugs most often involved in drug poisoning cases, and therefore, therapeutic drug monitoring (TDM) is necessary for safe and effective medication administration of these drugs. In this study, a coffee ring effect-based surface-enhanced Raman spectroscopy (CRE-SERS) method was developed and successfully used to monitor antipsychotic poisoning by using urine samples for the first time. The established method exhibited excellent SERS performance since more hot spots were obtained in the "coffee ring". Using the optimized CRE-SERS method, the sensitivity was improved one order more than that of the conventional method with reasonable reproducibility. The antipsychotic drug clozapine (CLO) spiked into urine samples at 0.5-50 µg mL-1 was quantitatively detected, at concentrations above the thresholds for toxicity. The CRE-SERS method allowed CLO and its metabolites to be ultimately distinguished from real poisoning urine samples. The coffee-ring effect would provide more opportunities for practical applications of the SERS-based method. The frequent occurrence of drug poisoning may have created a new area for the application of the CRE-SERS method. It is anticipated that the developed method will also have great potential for other drug poisoning monitoring.


Subject(s)
Antipsychotic Agents/urine , Clozapine/urine , Animals , Antipsychotic Agents/poisoning , Clozapine/poisoning , Male , Rats , Rats, Sprague-Dawley , Spectrum Analysis, Raman , Surface Properties
8.
Clin Toxicol (Phila) ; 54(6): 471-80, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27023487

ABSTRACT

CONTEXT: Use of second generation antipsychotics in England and Wales has increased in recent years whilst prescription of first generation antipsychotics has decreased. METHODS: To evaluate the impact of this change and of the withdrawal of thioridazine in 2000 on antipsychotic-related fatal poisoning, we reviewed all such deaths in England and Wales 1993-2013 recorded on the Office for National Statistics drug poisoning deaths database. We also reviewed antipsychotic prescribing in the community, England and Wales, 2001-2013. Use of routine mortality data: When an antipsychotic was recorded with other drug(s), the death certificate does not normally say if the antipsychotic caused the death rather than the other substance(s). A second consideration concerns intent. A record of "undetermined intent" is likely to have been intentional self-poisoning, the evidence being insufficient to be certain that the individual intended to kill. A record of drug abuse/dependence, on the other hand, is likely to have been associated with an unintentional death. Accuracy of the diagnosis of poisoning: When investigating a death in someone prescribed antipsychotics, toxicological analysis of biological samples collected post-mortem is usually performed. However, prolonged attempts at resuscitation, or diffusion from tissues into blood as autolysis proceeds, may serve to alter the composition of blood sampled after death from that circulating at death. With chlorpromazine and with olanzapine a further factor is that these compounds are notoriously unstable in post-mortem blood. Deaths from antipsychotics: There were 1544 antipsychotic-related poisoning deaths. Deaths in males (N = 948) were almost twice those in females. For most antipsychotics, the proportion of deaths in which a specific antipsychotic featured either alone, or only with alcohol was 30-40%, but for clozapine (193 deaths) such mentions totalled 66%. For clozapine, the proportion of deaths attributed to either intentional self-harm, or undetermined intent was 44%, but for all other drugs except haloperidol (20 deaths) the proportion was 56% or more. The annual number of antipsychotic-related deaths increased from some 55 per year (1.0 per million population) between 1993 and 1998 to 74 (1.5 per million population) in 2000, and then after falling slightly in 2002 increased steadily to reach 109 (1.9 per million population) in 2013. Intent: The annual number of intentional and unascertained intent poisoning deaths remained relatively constant throughout the study period (1993: 35 deaths, 2013: 38 deaths) hence the increase in antipsychotic-related deaths since 2002 was almost entirely in unintentional poisoning involving second generation antipsychotics. Clozapine, olanzapine, and quetiapine were the second generation antipsychotics mentioned most frequently in unintentional poisonings (99, 136, and 99 deaths, respectively). Mentions of diamorphine/morphine and methadone (67 and 99 deaths, respectively) together with an antipsychotic were mainly (84 and 90%, respectively) in either unintentional or drug abuse-related deaths. Deaths and community prescriptions: Deaths involving antipsychotics (10 or more deaths) were in the range 11.3-17.1 deaths per million community prescriptions in England and Wales, 2001-2013. Almost all (96%) such deaths now involve second generation antipsychotics. This is keeping with the increase in annual numbers of prescriptions of these drugs overall (<1 million in 2000, 7 million in 2013), largely driven by increases in prescriptions for olanzapine and quetiapine. In contrast, deaths involving thioridazine declined markedly (from 40 in 2000 to 10 in 2003-2013) in line with the fall in prescriptions for thioridazine from 2001. CONCLUSIONS: The removal of thioridazine has had no apparent effect on the incidence of antipsychotic-related fatal poisoning in England and Wales. That such deaths have increased steadily since 2001 is in large part attributable to an increase in unintentional deaths related to (i) clozapine, and (ii) co-exposure to opioids, principally diamorphine and methadone.


Subject(s)
Antipsychotic Agents/poisoning , Drug Recalls , Poisoning/mortality , Thioridazine/poisoning , Antipsychotic Agents/blood , Benzodiazepines/blood , Benzodiazepines/poisoning , Chlorpromazine/blood , Chlorpromazine/poisoning , Clozapine/blood , Clozapine/poisoning , England/epidemiology , Heroin/blood , Heroin/poisoning , Humans , Methadone/blood , Methadone/poisoning , Morphine/blood , Morphine/poisoning , Olanzapine , Poisoning/etiology , Quetiapine Fumarate/blood , Quetiapine Fumarate/poisoning , Thioridazine/blood , Wales/epidemiology
10.
Neth J Med ; 73(7): 345-7, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26314718

ABSTRACT

We report on a patient on clozapine treatment who was admitted to our hospital with pneumonia. He had stopped smoking a few weeks before admission. The serum clozapine rose to a toxic level, most likely due to the combination of infection and smoking cessation. Physicians and pharmacists are often not aware of risk factors for decreased metabolism of clozapine.


Subject(s)
Antipsychotic Agents/poisoning , Clozapine/poisoning , Empyema, Pleural/complications , Smoking Cessation , Antipsychotic Agents/blood , Clozapine/blood , Humans , Male , Middle Aged , Schizophrenia/drug therapy , Schizophrenia/metabolism
11.
Acta Biomed ; 85(2): 175-9, 2014 08 20.
Article in English | MEDLINE | ID: mdl-25245655

ABSTRACT

BACKGROUND AND AIM OF THE WORK: There has been an increasing amount of evidence to suggest a link between Clozapine and pneumonia. Whilst an exact mechanism for disease causation has not been identified excess salivation, impaired swallowing and abnormalities within the immune system have all been implicated. Within forensic services there is often a need to treat complex patients with Clozapine, even when a past history of pneumonia is present. METHODS: We present a case report on a forensic inpatient who has suffered repeated episodes of Clozapine associated pneumonia and highlight methods for good practice. RESULTS: Where appropriate, Clozapine can still be used in complex patients who have suffered previous pneumonias and have additional risk factors for chest infections, provided that robust risk reduction, infection surveillance and treatment interventions are employed. CONCLUSIONS: Practical measures can be employed to enable safe treatment of forensic patients with Clozapine, this includes risk factors for chest infections being carefully controlled such as asthma, Chronic Obstructive Airways Disease or diabetes. Patients should be carefully monitored for signs of infection by way of regular physical examinations and appropriate tests when required. Should signs of pneumonia arise the dose of Clozapine may need to be reduced and the infection aggressively treated with antibiotic medication.


Subject(s)
Clozapine/poisoning , Pneumonia/chemically induced , Schizophrenia/drug therapy , Antipsychotic Agents/poisoning , Antipsychotic Agents/therapeutic use , Clozapine/therapeutic use , Dose-Response Relationship, Drug , Humans , Male , Pneumonia/diagnosis , Young Adult
16.
Sud Med Ekspert ; 56(6): 41-6, 2013.
Article in Russian | MEDLINE | ID: mdl-25474921

ABSTRACT

This literature review is focused on diagnostics of acute clozapine intoxication with the fatal outcome. According to the Russian authors, clozapine intoxication ranks first in the structure of criminal poisoning and accounted for 99.7% of all the cases that occurred in Moscow during the period from 2003 to 2006. Toximetric investigations of clinical manifestations of clozapine intoxication revealed that the threshold clozapine concentration in blood is 0.12 ± 0.06 mg/I, the critical and lethal concentrations are 1.01 ± 0.2 mg/I and 3.5 ± 1.5 mg/I respectively. Autopsy on corpses of the victims of clozapine intoxication showed that most clozapine-induced pathological changes have a non-specific character (including largely circulatory disorders and dystrophic changes in parenchymatous organs). Clozapine poisoning is associated with the lengthening of QT-interval on ECG; at the values in excess of 500 ms, the risk of severe arrhythmia and sudden death significantly increases. Clozapine intake may lead to the development of potentially fatal myocarditis (the so-called clozapine-associated eosinophilic myocardium) in somatically healthy subjects. Foreign researchers report the possibility of a post-mortem increase of blood clozapine content compared with its antemortem level. They also showed that simultaneous use of substances stimulating activity of cytochrome P-450 enzymes (ethyl alcohol, finlepsin, fenitrin, nicotine) and clozapine accelerates metabolism and thereby reduces clozapine concentration in blood. It is concluded that comprehensive investigations of clozapine intoxication are needed taking into consideration pathomorphological changes induced by this agent, its potential interaction with other factors influencing human body, and the results of forensic chemical expertise of the fatal cases.


Subject(s)
Clozapine/poisoning , Crime , Forensic Toxicology/methods , Postmortem Changes , Clozapine/blood , Forensic Toxicology/legislation & jurisprudence , Humans , Poisoning/mortality , Poisoning/pathology
17.
J Clin Pharm Ther ; 38(2): 165-8, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23167664

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Clozapine, a second generation antipsychotic which is relatively safe in overdose, has been used as an effective treatment alternative to traditional antipsychotics. The therapeutic use in children remains controversial. However, in accordance with the increasing prescription in adults, the accidental ingestion in childhood becomes more frequent. We report the youngest case of accidental clozapine ingestion. CASE SUMMARY: A 13-month-old girl presented with acute respiratory insufficiency and coma of unknown origin. The medical history, laboratory and radiological assessment did not link to aetiology until an almost spontaneous arousal after 22 h pointed towards intoxication. The initial standard drug screening using immunoassay had been negative. Hence, liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS) was performed, and clozapine was detected with a serum concentration of 736 ng/mL. WHAT IS NEW AND CONCLUSION: This case illustrates the diagnostic and forensic pitfalls in a coma of unknown origin due to the limits of toxicological screening immunoassays. LC-MS/MS analysis by an established method showed clozapine metabolites (norclozapine and clozapine-N-oxide) are detectable for longer period, especially in urine, when compared with clozapine. The clinical course is presented in unique correlation with plasma and urine concentrations of clozapine and its metabolites. The elimination pattern of clozapine in toddlers is similar to adults, and the toxic dose was found to be lower when compared with school-age children and adults.


Subject(s)
Antipsychotic Agents/blood , Antipsychotic Agents/poisoning , Clozapine/blood , Clozapine/poisoning , Accidents , Antipsychotic Agents/pharmacokinetics , Clozapine/pharmacokinetics , Female , Humans , Infant
18.
Przegl Lek ; 69(8): 618-20, 2012.
Article in Polish | MEDLINE | ID: mdl-23243946

ABSTRACT

Pulmonary edema is a severe, potentially fatal clinical condition. It happens, when interstitial fluid is accumulating in the alveoli, impeding proper gas exchange. Typically we distinguish cardiogenic and noncardiogenic pulmonary edema. The article describes the case of severe pulmonary edema, which occurred in a young woman, free of cardiac diseases, about 30 hours after a suicidal drug poisoning (clozapine, ketoprofen, thiethylperazine). Both clozapine and ketoprofen intoxication, may be severe. Complications in these poisonings affect not only the central nervous system, but also the circulatory or respiratory system and may even occur several hours after the overdose of these drugs. The study considered the causes and possible mechanisms of pulmonary edema in poisoning with these drugs.


Subject(s)
Clozapine/poisoning , Ketoprofen/poisoning , Pulmonary Edema/chemically induced , Thiethylperazine/poisoning , Adult , Complex Mixtures/poisoning , Female , Humans , Suicide, Attempted
19.
Georgian Med News ; (204): 43-9, 2012 Mar.
Article in Russian | MEDLINE | ID: mdl-22573748

ABSTRACT

This article deals with materials, which have been received in the process of an examination and treatment of 69 patients with acute severe azaleptin (leponeks) poisonings. On the base of clinic data the special features of clinic of acute severe azaleptin (leponeks) poisonings has been shown. It has been registered that the using of substrate antihypoxant reamberin in the intensive therapy of severe forms of acute azaleptin (leponeks) poisonings led to significant improvement of clinic manifestations, such as a coma period duration, a duration of artificial lung ventilation, a period of holinolitic psychiatric violations and a decrease of lethal poisonings.


Subject(s)
Clozapine/poisoning , Meglumine/analogs & derivatives , Poisoning/drug therapy , Poisoning/pathology , Succinates/administration & dosage , Adult , Female , Humans , Male , Meglumine/administration & dosage , Middle Aged , Poisoning/mortality
20.
Aust N Z J Psychiatry ; 46(9): 816-25, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22327098

ABSTRACT

OBJECTIVE: To review the literature to examine the use of clozapine levels to (i) guide therapy and prevent toxicity in clinical care and (ii) determine cause of death in post-mortem examination of patients who were treated with clozapine. METHODS: MEDLINE was searched in December 2010 using the following keywords: 'clozapine levels', 'clozapine and toxicity', 'clozapine and death', 'clozapine and mortality' and 'post-mortem redistribution'. Data was also collected from the 2010 MIMS Annual. RESULTS: The literature reported significant variation in clozapine levels attained with any given dose, and considerable variability in the clinical response achieved at any given clozapine level. The lowest effective clozapine levels ranged from 250 to 550 µg/L, while the recommended upper limit to prevent toxicity varied from 600 to 2000 µg/L. There was minimal correlation between clozapine levels and side effects, with the exception of sedation, hypotension and seizure activity. The risk of seizures increased with plasma clozapine levels greater than 600 µg/L or rapid upward titration. In addition to prescribed dose, there are many factors that influence plasma clozapine levels. After death, the process of post-mortem drug redistribution resulted in 3.00 to 4.89 times increases in clozapine levels in central blood vessels and 1.5 fold increases in peripheral vessels compared to ante-mortem levels. CONCLUSIONS: The exact range of clozapine levels that corresponds to toxicity remains unclear. However, levels between 350 µg/L and 1000 µg/L achieved with gradual upward titration are more likely to be effective and less likely to cause toxicity. Ongoing clozapine level monitoring is indicated, especially when (i) prescribing higher doses (> 600 mg/day) of clozapine, (ii) there has been a change in a patient's concomitant pharmacotherapy or cigarette use and (iii) there has been a suboptimal response to treatment. The use of post-mortem clozapine levels to determine clozapine toxicity as a cause of death is unreliable.


Subject(s)
Antipsychotic Agents/blood , Cause of Death , Clozapine/blood , Psychotic Disorders/drug therapy , Antipsychotic Agents/adverse effects , Antipsychotic Agents/therapeutic use , Autopsy , Clozapine/adverse effects , Clozapine/poisoning , Clozapine/therapeutic use , Humans
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