Preventable deaths involving antipsychotics: a systematic case series of coroners’ reports in England and Wales 2013-2021
Creators: name: Bilku, Simran
name: Richards, Georgia
name: Cox, Anthony
name: France, Harrison
Publisher: name: Open Science Framework
Year: 2022
Subjects: subject: Medicine and Health Sciences
subject: antipsychotic drugs
subject: coroner reports
subject: preventable deaths

description: Antipsychotic drugs are a class of drugs predominately used in the treatment of individuals with psychotic disorders, including schizophrenia, delusional disorder and bipolar affective disorder (Lally and MacCabe, 2015). All antipsychotic drugs act as D2 receptor antagonists (Lally and MacCabe, 2015). D2 receptors are a type of dopamine receptor expressed in the striatum, the nucleus accumbens and the olfactory tubercle. They are also present in the substantia nigra, ventral tegmental area, hypothalamus, cortical areas, septum amygdala and the hippocampus (Aringhieri et al., 2018). The dopaminergic system has a key role in the pathogenesis of schizophrenia (Aringhieri et al., 2018). The ‘dopamine hypothesis’ states there is an excess of dopaminergic activity in the mesolimbic pathway, causing what’s known as positive symptoms, and reduced dopaminergic activity in the mesocortical pathway, causing negative symptoms. The development of antipsychotic drugs began with the discovery of chlorpromazine in 1952. This led to the development of what is now known as first-generation/typical antipsychotic drugs, first introduced between 1954 and 1975 (Shen, 1999). First-generation antipsychotic drugs were found to cause debilitating extrapyramidal side effects (EPSEs) and so second-generation (also known as atypical) antipsychotic drugs were developed. Second-generation antipsychotic drugs are less likely to cause EPSEs when taken at moderate doses (Lally and MacCabe, 2015). Clozapine was introduced in 1990, and was the model for the development of second-generation antipsychotic drugs (Shen, 1999). Clozapine is the gold standard for the treatment of refractory schizophrenia and is unique in that it is the only antipsychotic drug proven to be effective against treatment-resistant schizophrenia, however the benefits of clozapine are outweighed by risks of adverse side effects (Lally and MacCabe, 2015; Aringhieri et al., 2018). There are currently 8 second-generation licensed for use in the UK: amisulpride, aripiprazole, clozapine, lurasidone, olanzapine, paliperidone, quetiapine and risperidone (Lally and MacCabe, 2015; Antipsychotic medicines, 2005). Second-generation antipsychotics differentiate from first-generation antipsychotics in that whilst being weak D2 receptor antagonists, they also target other receptors and neurotransmitters such as the 5-HT2c and 50HT1A serotonin receptors. Long-term use of second-generation antipsychotics has been shown to have complex effects on neuronal functionality mediated by intracellular mechanisms involved in activation of pathways such as extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein Kinase B (Akt). Newer studies have demonstrated how second-generation antipsychotics differ from first-generation through activation of specific functions of the 5-HT2A receptor. Another differentiating mechanism is the fast dissociation (Koff) of second-generation antipsychotics from dopamine D2 receptors; this explains the lowered tendency towards adverse effects such as parkinsonism and hyperprolactinemia seen in first-generation antipsychotics (Aringhieri et al., 2018). Treatment with antipsychotics is often a trade-off between alleviation of psychotic symptoms and potential complications. Such complications can sometimes be life-threatening adverse effects. Examples of complications include sedation, sexual dysfunction, postural hypotension, cardiac arrhythmia and sudden cardiac death. First-generation antipsychotic drugs are associated with risk of movement disorders and anticholinergic effects such as constipation, urinary retention, dry mouth, blurred vision and cognitive impairment (Muench and Hamer, 2010). Some complications associated with second-generation antipsychotics are metabolic syndrome: obesity, glucose intolerance and dyslipidemia. Clozapine is the most strongly linked antipsychotic drug with metabolic syndrome (Siafis et al., 2018). The life expectancy of individuals with schizophrenia is approximately 10-25 years less than the general population; a significant contributor to this lowered life expectancy being sudden unexpected death. The cause of 15-40% of sudden unexpected deaths in patients with schizophrenia is sudden cardiac death (SCD) (Li, Greenstein and Delisi, 2018). SCD can be an adverse effect of antipsychotic drugs (Zhu, 2019). It is defined as death due to cardiac cause within a short period (minutes to hours) of onset of clinical symptoms (Li, Greenstein and Delisi, 2018). SCD is often a result of ventricular tachyarrhythmia- most commonly ventricular fibrillation (Zhu, 2019). Studies have shown a link between use of antipsychotic drugs and increased mortality of SCD in individuals with psychiatric disorders. They demonstrated users of first-generation and second-generation antipsychotic drugs to have a higher incidence of SCD than non-users, with former users showing no significant increased risk. They also found the risk of SCD to increase in a dose-dependent manner (Ray et al., 2009). All antipsychotic drugs inhibit potassium channels in the ventricles and can contribute to prolongation of ventricular repolarization, leading to SCD (Zhu, 2019; Muench and Hamer, 2010). Clozapine has been shown to have the highest risk of SCD as a complication, followed by risperidone and then olanzapine (Li, Greenstein and Delisi, 2018). It is important to implement management of SCD in patients taking antipsychotic medication, in order to help prevent future deaths. The most effective treatment for high-risk individuals of SCD/survivors of SCD are implantable cardioverter defibrillators. It is important to begin patients on antipsychotic medications with the lowest effective dose and constantly monitor for arrhythmia. Wearable medical devices can also be worn by patients; these devices monitor heart rate and take ECGs using AI technology (Zhu, 2019). Care should also be taken when treating patients with combination antipsychotics, and physicians should avoid combining antipsychotic medications with other medications that prolong ventricular repolarization (Lally and MacCabe, 2015; Muench and Hamer, 2010). Coroners in England and Wales must report and communicate details of deaths when they believe that actions should be taken to prevent future deaths. These reports, named Prevention of Future Deaths reports (PFDs), involve three processes: 1) coroners write PFDs highlighting concerns and address reports to specific individuals or organisations; 2) addressees respond to the concerns raised in PFDs within 56 days; 3) the actions taken (or proposed) are explained and implemented. However, this process and the statutory requirement of responding to PFDs and taking action is not audited, and concerns have been raised regarding the lack of wider communication of the lessons reported in PFDs. PFDs have been analysed to examine preventable deaths involving cardiovascular disease and anticoagulants, the covid-19 pandemic, cyclists, suicides, medicines and drugs of misuse, including an analysis of opioid-related deaths. However, PFDs involving antipsychotics have not been assessed.