clozapine and Poisoning

Use of second generation antipsychotics in England and Wales has increased in recent years whilst prescription of first generation antipsychotics has decreased.. 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 entirel. 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.

Topics: Antipsychotic Agents; Benzodiazepines; Chlorpromazine; Clozapine; Drug Recalls; England; Heroin; Humans; Methadone; Morphine; Olanzapine; Poisoning; Quetiapine Fumarate; Thioridazine; Wales

The aim of this review was to determine the spectrum and severity of effects of unintentional antipsychotic poisoning in children. A computerised literature search of MEDLINE (1966 to February 2005) and EMBASE (1980 to February 2005) was undertaken. The Internet was searched using URL: www.google.com. The proceedings of the North American Congress of Clinical Toxicology (NACCT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) were hand searched. All cases of unintentional antipsychotic (all classes) poisoning in children aged 0-6 years were included. The data extracted included the age, weight, antipsychotic, dose, clinical effects, treatment and outcomes. The toxic dose was estimated as the lowest dose causing objective adverse effects.Sixty-eight reports were identified. Few contained all of the required information. Most of the case series included multiple antipsychotics with limited information on individual drugs or all ages with limited paediatric information. For most antipsychotics the ingestion of one tablet caused symptoms that were sometimes severe and usually lasted from 1 to 3 days. Extrapyramidal symptoms (EPS) were often delayed for up to 12-24 hours. Chlorpromazine caused CNS depression, hypotension and miosis; EPS and cardiac effects were rare, and the toxic dose was estimated to be 15 mg/kg. Haloperidol caused drowsiness (rarely coma) and over one-half of patients had neuromuscular effects (mainly EPS), with a toxic dose estimated at 0.15 mg/kg. Thioridazine caused CNS depression and potentially cardiac effects, with a toxic dose of 1.4 mg/kg. Atypical antipsychotics caused significant CNS depression (except risperidone); EPS were less common. Toxic doses were clozapine 2.5 mg/kg, olanzapine 0.5 mg/kg and aripiprazole 3 mg/kg. EPS responded to anticholinergic drug treatment. In summary, unintentional antipsychotic ingestion in children can cause severe effects that last 1-3 days, often with one tablet. Children potentially ingesting a toxic dose or who are symptomatic should be considered for assessment in hospital. Most cases resolve with good supportive care. Toxic doses are only estimates that are based on limited data and should be used with caution until prospective studies are undertaken.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Child; Child, Preschool; Chlorpromazine; Clozapine; Dibenzothiazepines; Haloperidol; Humans; Infant; Infant, Newborn; Olanzapine; Pimozide; Piperazines; Poisoning; Quetiapine Fumarate; Quinolones; Risperidone

Clozapine (Clozaril) and olanzapine (Zyprexa) are two relatively new atypical antipsychotics that are structurally and pharmacologically related. There are currently no therapeutic indications for these pharmaceuticals in infants and toddlers.Presumably, as the usage of these medications in adults increases, the frequency of unintentional pediatric ingestions will increase. In 2001 the annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System included a separate subcategory for atypical antipsychotics under the heading of sedatives/hypnotics/antipsychotics. The toxidrome resulting from these drugs is predominately central nervous system depression and anticholinergic effects. Although the desirable lack of extrapyramidal symptoms in adults results in their greatest clinical utility, several reports of toxic ingestions in small children are noteworthy for having extrapyramidal manifestations. We review here the available reported clinical experience with toxic doses of these medications that in small children may amount to as little as a single tablet. Although such doses may be lethal, supportive care and gastrointestinal decontamination in this population will generally lead to a good outcome.

Topics: Antipsychotic Agents; Benzodiazepines; Child, Preschool; Clozapine; Dose-Response Relationship, Drug; Humans; Infant; Olanzapine; Poisoning

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).. This study aimed to assess the adjuvant therapeutic role of SMOF Lipid administration on the outcomes of acute clozapine poisoning.. 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.. 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).. 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.

Topics: Adolescent; Adult; Antidotes; Antipsychotic Agents; Child; Child, Preschool; Clozapine; Combined Modality Therapy; Egypt; Fat Emulsions, Intravenous; Female; Fish Oils; Humans; Male; Olive Oil; Poisoning; Soybean Oil; Treatment Outcome; Triglycerides; Young Adult

In this article there are materials, which were received in the process of treatment of 69 patients with azaleptin (leponeks) acute severe poisonings. The immunologic research has shown that the first phase of acute poisonings in patients with toxicohypoxic encephalopathy is accompanied by severe immune alterations. The alterations of proinflammation and antiinflammation cytokines have been investigated and its increase has not been revealed. It was shown, that the employment of citoflavin in intensive therapy of acute poisonings leads to decrease of the level of immunosupression.

Topics: Blood Cell Count; Clozapine; Critical Illness; Drug Combinations; Female; Flavin Mononucleotide; Humans; Hypoxia, Brain; Immune System; Inosine Diphosphate; Male; Neurotoxicity Syndromes; Niacinamide; Poisoning; Succinates

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.

Topics: Adult; Clozapine; Female; Humans; Male; Meglumine; Middle Aged; Poisoning; Succinates

The Danish Poison Information Centre (DPIC) provides information to the public and health care professionals on acute poisonings. The DPIC received 41,000 enquiries during the first three years of its existence as an open 24h telephone service. The aim of this data register study was to classify all substance exposures, to gain knowledge of the status and trends in poisonings (toxico-surveillance) and to evaluate the development in the number of contacts.. Information and inquiries were continuously entered into a poison-centre database. A new classification system was established during the study to ensure that all agents were properly classified. A total of 41,139 calls were divided into 18 substance categories, each consisting of 3-11 subgroups.. The number of contacts per year increased by 70% from 2007 to 2009. Three contacts per thousand individuals in the Danish population were registered in 2009. For all groups, except drugs of abuse, the data showed an increase in the actual number of exposures from 2008 to 2009. Pharmaceuticals represent one third of substance exposures, and analgesics constitute a third of these poisonings. A relative increase in contacts concerning household substances, plants and vitamins was observed.. The classification gave detailed knowledge of the current poisoning status. Evaluation of subgroups showed a need for a larger number of subgroups to ensure a sufficient level of toxico-surveillance. Compared to other national poison centres, we predict a doubling in enquiries during the next ten years, mainly from the public.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Clozapine; Denmark; Hotlines; Household Products; Humans; Iron; Plants; Poison Control Centers; Poisoning; Psychotropic Drugs; Registries; Vitamins

18 patients with acute clozapine poisoning, 6 female and 12 male, were analyzed. The mean age was 42.8 years. Six patients were intoxicated only clozapine. Mixed poisoning (clozapine and other factor) was diagnosed in nine cases. Among the additional factors dominated psychotropic drugs. According to the Poisoning Severity Score (PSS) criteria in the study group was only a one mild intoxication. Acute pneumonia developed in 3 patients, acute bronchitis and rabdomyolysis were reported in one case. The most common symptoms included: agitation, confusion (83.3%), tachycardia (77.8%), CNS depression (66.7%), excessive mucus production in bronchi, hypersalivation (44.4%), miosis (50%). Disordered breathing requiring intubation or mechanical ventilation occurred in 27.7% of poisoned. The average duration of hospitalization was less than 7 days.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Length of Stay; Male; Poisoning; Poland; Retrospective Studies

Acute poisonings by medical, narcotic substances and alcohol are actual in Russia in the recent years. Comparison of analytic facilities of modern analytical techniques: chromatographic (HPLC, GC, GC-MS) and immuno-chemical (FPIA) in clinical toxicology for urgent diagnostics, assessment of the severity of acute poisoning and the efficacy of the treatment in patients with acute poisonings by psychotropic drugs, narcotics and alcohol have been done. The object of the study were serum, blood, urine of 611 patients with acute poisonings by amitriptyline, clozapine, carbamazepine, opiates and also alcohol. Threshold concentrations (threshold, critical and lethal) of the toxicants and their active metabolites which corresponded to different degrees of poisoning severity have been determined. The most comfortable and informative screening method for express diagnostics and assessment of severity of acute poisonings by psychotropic drugs and narcotics showed the HPLC with using automatic analyzers. FPIA using the automatic analyzer could be applied for screening studies, if group identification is enough. GC-FID method is advisable in case of poisoning by medical substances and narcotics in view of repeated investigation for assessment of the efficacy of the therapy. GC-MS could be advisable for confirming the results of other methods. GC-TCD possess high sensitivity and specificity and is optimal for express differential diagnostics and quantitative assessment of acute poisoning by ethanol and other alcohols.

Topics: Acute Disease; Amitriptyline; Carbamazepine; Central Nervous System Agents; Clozapine; Ethanol; Female; Humans; Immunoenzyme Techniques; Male; Mass Spectrometry; Narcotics; Poisoning; Reproducibility of Results; Russia; Severity of Illness Index; Substance Abuse Detection; Substance-Related Disorders; Toxicology

Toxicological analyses are often performed to investigate suspected poisoning, but the interpretation of results may not be straightforward. We studied suspected poisoning cases 1992-2003 where blood clozapine and N-desmethylclozapine (norclozapine) were measured in order to assess the relationship of these parameters to outcome.. Samples were referred from clinicians, pathologists/coroners, or via the Clozaril Patient Monitoring Service (CPMS, Novartis). Information was gathered from clinical, post-mortem, or coroners' reports.. There were seven fatal [five male, two female; median (range) age 28 (24-41) year] and five non-fatal [four male, one female; median age 35 (26-41) year] clozapine overdoses. The median post-mortem blood clozapine and norclozapine concentrations were 8.2 (3.7-12) and 1.9 (1.4-2.4)mg/L, respectively [median clozapine:norclozapine ratio 4.4 (2.9-5.1)]. The median plasma clozapine and norclozapine concentrations (first or only sample) were 3.9 (1.7-7.0) and 0.40 (0.30-0.70)mg/L, respectively [median clozapine:norclozapine ratio 7.6 (5.3-18)] in the remainder. These overdoses were in patients who were poorly or non-adherent to clozapine, or who had taken tablets prescribed for someone else. In 54 further people who died whilst receiving clozapine [38 male, 16 female; median age 41 (22-70) year], the median post-mortem blood clozapine and norclozapine concentrations were 1.9 (0-7.7, n = 43) and 1.4 (0-6.0, n = 39)mg/L, respectively [median clozapine:norclozapine ratio 1.5 (0.4-7.6, n = 38)]. The median post-mortem increase in blood clozapine and norclozapine as compared to the most recent ante-mortem measurement was 489 (98-5,350)% and 371 (139-831)%, respectively [median sample time before death 14 (0-30, n = 21) days].. Clozapine poisoning cannot be diagnosed on the basis of blood clozapine and norclozapine concentrations alone. The analysis of ante-mortem blood specimens collected originally for white cell count monitoring and the blood clozapine:norclozapine ratio may provide additional interpretative information.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Drug Overdose; Female; Forensic Medicine; Humans; Leukocyte Count; Male; Middle Aged; Poisoning; Postmortem Changes; Suicide; Treatment Refusal; United Kingdom

Topics: Adolescent; Adult; Antihypertensive Agents; Antipsychotic Agents; Calcium Chloride; Clonidine; Clozapine; Diagnosis, Differential; Drug Combinations; Humans; Hyperbaric Oxygenation; Poisoning; Sorption Detoxification; Vitamin D

Topics: Agranulocytosis; Case Management; Clozapine; Female; Humans; Lithium; Male; Poisoning; Psychotropic Drugs

Topics: Adult; Arsenic Poisoning; Cause of Death; Child, Preschool; Clozapine; Diagnosis, Differential; Drug Overdose; Expert Testimony; Fat Emulsions, Intravenous; Female; Homicide; Humans; Infant; Insanity Defense; Male; Middle Aged; Poisoning; Poisons; Postmortem Changes; Strychnine