Investigating clozapine health outcomes using electronic health records

Student thesis: Doctoral ThesisDoctor of Philosophy



Clozapine is the only evidence-based medication for treatment-resistant schizophrenia. However, clozapine is severely under-prescribed mainly because of clozapine-induced agranulocytosis, an adverse drug reaction of clozapine that occurs in 0.4% of clozapinetreated patients. Since there are no clinical predictors for clozapine-induced agranulocytosis, all clozapine users are required to be under strict blood test monitoring throughout the duration of their clozapine treatment.

Aims of this thesis

To use data from electronic health records to test the following hypothesis:
(i) Predictors for clozapine-induced agranulocytosis can be investigated using the
results of the analysed electronics health records data published in (Iqbal et al.,
(ii) The frequency density of clozapine blood test results that indicate clozapineinduced agranulocytosis risk changes with clozapine treatment time
(iii) Clozapine-treated patients are at an increased risk of COVID-19 infection
(iv) Clozapine-treated patients are at an increased risk of severe outcomes of COVID-19 infection


All data were extracted from Clinical Record Interactive Search (CRIS), the de-identified electronic health records of South London and Maudsley NHS Foundation Trust (SLAM). All data extraction was performed using SQL. All analysis was performed using either R, python or STATA. The statistical methods used in this thesis are logistic regression, survival analysis and Cox proportional hazard models.


We found that the data from (Iqbal et al., 2020) was not informative for investigating predictors for clozapine-induced agranulocytosis, thus this study did not bear any significant results. However, it helped us to realise that the next step was to study the patterns of clozapine blood monitoring data.

From studying the patterns in clozapine blood monitoring results, we showed that the highest risk of clozapine-induced agranulocytosis is in the early months of treatments. The Kaplan-Meier survival curve and the incidence rates analysis showed that 75% of blood test results that indicated clozapine-induced agranulocytosis risk occurred within the first 6 months of clozapine treatment.

At the onset of the COVID-19 pandemic, we investigated the associations between clozapine treatment and increased risk of COVID-19. We found that clozapine-treated patients had an increased risk of COVID-19 compared with those who were on other antipsychotic medication (unadjusted HR = 2.62, 95% CI 1.73 - 3.96), which was attenuated after adjusting for potential confounders, including clinical contact (adjusted HR=1.76, 95% CI 1.14 - 2.72).

We followed up on the previous study to investigate the associations between clozapine treatment and increased risk of severe outcomes of COVID-19, namely COVID-related hospitalisation, COVID-related intensive care treatment, and death. We found that even though clozapine treatment appears to increase the risk of COVID-19 infection, it does not increase the risk of the severe outcomes of COVID-19.


In conclusion, electronic health records are a valuable resource for studying clozapine health outcomes. In particular, the CRIS data is a very informative resource for answering research questions related to mental health disorders.

Date of Award1 Jun 2022
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorRichard Dobson (Supervisor), Cathryn Lewis (Supervisor) & James Maccabe (Supervisor)

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