Rani, Fariz Abdul; (2009) Utilisation and safety of antipsychotic medicines in the young. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Antipsychotic medications are used for the treatment of various psychiatric disorders, including psychotic disorders such as schizophrenia. There are two main classes of antipsychotic drugs; the older, typical antipsychotics and the newer atypical antipsychotics. Studies in the USA and the Netherlands show that antipsychotic use in children is rising, primarily for 'off-label' indications. Thus, despite the evident increase in use, the safety profile of these drugs in this population is lacking. Furthermore, there is a gap in investigations of antipsychotic use and safety in the UK paediatric population. Therefore, the aim of this thesis was to investigate the utilisation and safety of antipsychotic medications in children and adolescents in the UK. Three main studies were conducted. Firstly, the pharmacoepidemiology of antipsychotic prescribing in the paediatric population was examined using the General Practice Research Database (GPRD). Secondly, the incidences of specific serious adverse events of mortality, liver abnormalities, diabetes mellitus and extrapyramidal effects in the identified GPRD cohort exposed to antipsychotic therapy was investigated. Finally, a targeted pharmacovigilance pilot study was conducted to describe adverse reactions associated with atypical antipsychotic treatment seen in children from secondary and tertiary care settings. The feasibility of conducting the pharmacovigilance study, with the view of expanding it to a wider scale, was also explored. The largest UK paediatric cohort exposed to antipsychotic therapy was identified from the GPRD. The overall prevalence of antipsychotic prescribing almost doubled between 1992 and 2005 (0.39 to 0.77 patients per 1,000 person-years). The greatest increase was seen in patients aged 7-12 years (0.23 patients per 1,000 person-years in 1992 and 0.61 patients per 1,000 person-years in 2005). Atypical antipsychotic agents were shown to be replacing the older, typical antipsychotics. Although there was an increasing prevalence trend, the incidence of all antipsychotic prescribing remained stable suggesting patients stay on treatment for longer durations. Results from the safety studies revealed that children exposed to antipsychotic therapy have a higher mortality rate than the general paediatric population (SMR of 4.03; 95% CI; 1.48 to 8.76). However, it was demonstrated that antipsychotic therapy was unlikely to be associated with the majority of the identified cases of death. The rate of diabetes mellitus was not significantly different compared to the general paediatric population (SIR of 1.61; 95% CI: 0.20 to 5.81) and there were also no cases of liver adverse reactions in the antipsychotic-exposed cohort. However, these results were possibly limited by the sample size of the study cohort. On the other hand, antipsychotic-exposed patients were shown to have significantly higher odds ratios of experiencing extrapyramidal symptoms compared to unexposed patients (OR of 1.88; p < 0.05). The targeted pharmacovigilance study on atypical antipsychotics allowed for an alternative method for investigating the safety of these drugs in children. The study revealed a high rate of adverse drug reactions with every five patients experiencing a reaction. The study also identified relevant methodological issues which need to be addressed related to expanding such a study to wider scale.

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