Fatalities Associated with Therapeutic Use and Overdose of Atypical Antipsychotics

Abstract

Since 1989, several novel antipsychotic drugs have become available for use including clozapine, risperidone, olanzapine, quetiapine and ziprasidone. These agents represent a substantial improvement in the treatment of schizophrenia and related disorders and are considered to have a favourable adverse effect profile relative to traditional antipsychotics. Nonetheless, in rare cases, people have died as a result of taking atypical antipsychotic drugs at therapeutic and supratherapeutic doses. Toxic doses of atypical antipsychotics are highly variable: some patients have died while taking therapeutic doses and others have survived massive overdoses. Toxicity may be increased by coingestion of other agents, particularly drugs with similar metabolic pathways. Atypical antipsychotics are metabolised predominantly by cytochrome p450 (CYP) isoenzymes, particularly CYP1A2 (clozapine and olanzapine), CYP3A4 (clozapine, quetiapine and ziprasidone) and CYP2D6 (olanzapine and risperidone). Concurrent prescription of other drugs that inhibit these isoenzymes may increase the probability of adverse events in patients taking atypical antipsychotics. Deaths due to atypical antipsychotic toxicity are often related to cardiovascular complications, but pulmonary, neurological, endocrine and gastrointestinal complications have also caused fatalities. Prevention and management of atypical antipsychotic overdose are of increased clinical relevance as prescription of these drugs increases.

A validated GC/MS method for the investigation of quetiapine-related deaths in Greece

“…Quetiapine was determined at concentrations higher than 600 ng/mL in 13 cases, at toxic levels (>1800 ng/mL) in 8 cases and at lethal level in one case (14112 ng/mL), whereas in 29 cases, its concentration was within the therapeutic range and in 8 cases at sub-therapeutic levels. These results reveal that quetiapine shows a highly variable range of toxicity and support previous published studies suggested that deaths can be occurred even with therapeutic doses [14,18,44,45]. Several factors may contribute to this variability, such as increased susceptibility of the individuals and co-ingestion of other drugs [18].…”

Multiple drugs poisoning resulting in ARDS

“…Bizim olgumuzdaki karbamazepin dozu 35 mg/kg idi, nörolojik ve kardiak hiçbir semptom görülmedi. Antipisikotik ve antidepresan ilaçların ARDS'yi tetikleyebildiği bilinse de bununla ilgili vaka sayısı çok fazla değildir [9] . Bu araştırmalarda ARDS'ye neden olan patofizyolojik mekanizmayı açılayabilecek net bir neden olmasa da nöroleptik malign sendromun bir komponenti, nörojenik pulmoner ödem [10] akciğer dahil birçok dokuda nötrofillerin aktivasyonunu içeren bir alerjik reaksiyon [11] ve dozla ilişkili etki olduğu öne sürülmüştür.…”

Use of Antipsychotics to Treat Cocaine Toxicity?

“…2,3 They may also lower the seizure threshold. 4 Furthermore, both cocaine 5,6 and ziprasidone 7,8 prolong the QT interval, which may cause lethal dysrhythmias if combined. We therefore disagree with the authors' assertion that safety is implied in the setting of cocaine toxicity because the use of antipsychotics demonstrates a lack of ''significant adverse events with widespread use.''…”