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Mortality in Children and Adolescents Prescribed Antipsychotic Medication

A Retrospective Cohort Study Using the UK General Practice Research Database

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Abstract

Background: Antipsychotic prescribing in children has risen in many countries; however, the safety of these agents in the young has not yet been fully established. Potentially fatal antipsychotic-related adverse events include cardiac complications and neuroleptic malignant syndrome.

Objective: The objective of this study was to investigate mortality in children and adolescents taking antipsychotic medication.

Methods: The General Practice Research Database (GPRD) was used as a data source for this study. Cases were identified from a cohort of patients previously studied. The study population encompassed all patients aged 18 years and under who received at least one prescription for an antipsychotic from 1 January 1992 to 31 December 2005. Patients were followed from the date of the first antipsychotic drug prescription until the earliest occurrence of a code of death, age >18 years or the end of the study period. Cases of death were identified by screening patients’ medical records for clinical or referral events with events indicating death, or if a transferred-out patient has a ‘transfer out reason’ specified as ‘death’. Confirmation of cases was carried out by examining individual patient profiles and from questionnaires sent to GPs. If necessary, the death certificates and/or post mortem reports were obtained by the source data verification service the GPRD provide. Once cases of death were identified, crude mortality rate (CMR) and standardized mortality ratio (SMR) were calculated. Baseline mortality rates were obtained from the Office for National Statistics. A modified WHO causality assessment was conducted to determine the likelihood of a relationship between the drug and an event of death.

Results: The cohort contained 2767 patients who received at least one antipsychotic prescription. There were 30 deceased cases in the cohort. The GP questionnaire response rate was 97%. Of the 30 cases, 24 were related to preexisting medical conditions, including neoplastic diseases and HIV. After excluding these patients, six cases of death from 5963 person-years and 1958 treatment-years remained. The median age of death was 17 years (interquartile range 14–17.75). The overall CMR was 1.01 per 1000 person-years at risk (95% CI 0.20, 1.81) and SMR was 4.03 (95% CI 1.48, 8.76). Of the six cases, only one was deemed possibly associated with antipsychotic therapy, based on the causality assessment analysis conducted; CMR based on this case was 0.51 per 1000 treatment-years (95% CI 0.09, 2.89). The remaining five cases of death were unlikely to be associated with antipsychotic therapy.

Conclusions: Our study demonstrated an elevated SMR in patients exposed to antipsychotics. However, the elevated SMR was unlikely caused by antipsychotic treatment, but would suggest the possibility of inadequate management or poor control of patients’ underlying medical conditions prior to death.

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Acknowledgements

The authors would like to sincerely thank the GPRD verification team and staff at the ONS for providing the additional data for this study. We also thank all the GPs who contributed data to the GPRD, and those who contributed data to this study.

Funding: The license for the GPRD was funded by the European Commission via the Taskforce European Drug Development for the Young (TEDDY) network of Excellence European Commission Framework 6 Programme (2005–10). Professor Wong was supported by a Department of Health Public Health Career Scientist Award in England. Dr Rani was supported by a scholarship from the Ministry of Higher Education of Malaysia. The study was conducted independently from the above funding providers.

Contributors: Ian C.K. Wong, Fariz A. Rani and Macey L. Murray conceived the idea of the study. All authors were involved in the study design. Fariz A. Rani, Patrick Byrne, Noel Cranswick and Ian C.K. Wong analysed the data. All authors were involved in the interpretation of the data, had full access to the study data and take responsibility for the integrity of the data and accuracy of the data analysis. All authors drafted, revised and approved the final manuscript. Ian C.K. Wong is the guarantor.

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Authors and Affiliations

  1. Centre for Paediatric Pharmacy Research, School of Pharmacy, University of London, London, UK

    Fariz A. Rani, Macey L. Murray &  Ian C.K. Wong

  2. Institute of Child Health, University College London, London, UK

    Fariz A. Rani, Macey L. Murray &  Ian C.K. Wong

  3. Department of Pharmacy, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia

    Fariz A. Rani

  4. Institute of Psychiatry, King’s College London, University of London, London, UK

    Patrick Byrne

  5. Australian Paediatric Pharmacology Research Unit, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia

    Noel Cranswick

  6. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, 2/F Laboratory Block, Hong Kong, Hong Kong

    Ian C.K. Wong

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  1. Fariz A. Rani
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  2. Patrick Byrne
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  3. Noel Cranswick
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  4. Macey L. Murray
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  5. Ian C.K. Wong
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Correspondence to Ian C.K. Wong.

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Rani, F.A., Byrne, P., Cranswick, N. et al. Mortality in Children and Adolescents Prescribed Antipsychotic Medication. Drug-Safety 34, 773–781 (2011). https://doi.org/10.2165/11591120-000000000-00000

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