To investigate the safety and effectiveness of antipsychotics in chronic and acute treatment : through observational studies and experimental study (randomised clinical trial)

Abstract

Antipsychotic is one of the most commonly used psychotropic drug class. As the utilisation of antipsychotics has been increasing, safety and effectiveness concerns on the use of antipsychotics have been highlighted. However, population-level evidence on the safety and effectiveness for chronic and acute treatment of antipsychotics in general mental patients and vulnerable patient groups is lacking. This thesis aims to investigate the safety and effectiveness of antipsychotics in chronic and acute treatments through observational studies and a randomised clinical trial. The primary objectives of respective chapters in this thesis are to investigate: 1) the drug utilisation, the mortality risk in chronic treatment, and risk of neuroleptic malignant syndrome acutely after treatment initiation by multiple population-based observational study designs, and 2) the effectiveness and safety of short-acting injections in managing acute agitation in the emergency settings by a multicentre double-blinded randomised clinical trial. Clinical data from the Hong Kong Clinical Data Analysis and Reporting System, and data prospectively collected from patients recruited for the trial was used in this thesis. The results of these studies were then compared to the literature for discussion. First, this thesis reports a cross-sectional descriptive utilisation study in Hong Kong. Antipsychotics have been increasingly prescribed in the general population, children, and older patients. There was an increase in second-generation antipsychotic prescribing. The prescription volume of first-generation antipsychotics haloperidol is notably higher in Hong Kong compared to overseas settings. Secondly, this thesis reports an association between antipsychotics and mortality risk in long-term using a population-based cohort. We observed that haloperidol is associated with increased mortality risk in a long-term exposure period time over other antipsychotics. Thirdly, a randomised clinical trial on the safety and effectiveness of intramuscular antipsychotics in managing acute agitation in the emergency setting is presented. The results of the interim analysis suggested the generally equivalent effectiveness between the novel choice of sedative olanzapine, and conventional sedatives haloperidol or midazolam. The final part of the thesis presents a case-crossover study on the risk of the neuroleptic malignant syndrome in antipsychotic users in Hong Kong, through a case-crossover study using a population-based cohort. The initiation of antipsychotic medication, haloperidol and quetiapine were associated with an acutely increased risk of developing NMS, but not risperidone or olanzapine. Findings of the thesis demonstrate a particularly high prevalence of haloperidol prescribing in Hong Kong despite the increasing use of second-generation antipsychotics. However, a consistently higher risk of premature mortality and neuroleptic malignant syndrome associated with haloperidol was observed. The interim results of randomised clinical trial suggested generally comparable effectiveness among olanzapine, midazolam, and haloperidol. Various pharmacoepidemiological methodologies using the healthcare databases provide access to high-level research evidence to broaden the understanding of antipsychotic safety and inform clinical practice of prescribing antipsychotic especially haloperidol. Future research direction is to combine with different databases/study sites for a more significant sample size to obtain extra robustness and strengthen generalisability of the findings.