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Title: Examining treatment response and adverse effects of clozapine
Author: Legge, Sophie E.
ISNI:       0000 0004 5915 2658
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2015
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The antipsychotic clozapine is uniquely effective in the management of treatmentresistant schizophrenia (TRS), but its use is limited by its potential to induce agranulocytosis. A substantial proportion of patients discontinue clozapine treatment, which carries a poor prognosis, and only 30-60% of patients with TRS will respond to clozapine. The causes of clozapine-associated agranulocytosis, and of its precursor neutropenia, are largely unknown although genetic factors contribute. To examine the genetic susceptibility to clozapine-associated neutropenia, I conducted a multifaceted genetic analysis in the largest combined sample studied to date. Using GWAS, I identified a novel genome-wide significant association with rs149104283 (OR = 4.32, P = 1.79x10-8), a SNP intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes involved in drug uptake. Furthermore, I replicated a previously reported association between neutropenia and a variant in HLA-DQB1 (OR = 15.6, P = 0.015). I investigated clozapine discontinuation and clinical response in a two-year retrospective cohort study of 316 patients with TRS receiving their first course of clozapine. By studying the reasons for discontinuations due to a patient decision, I found that adverse drug reactions accounted for over half of clozapine discontinuations. High levels of deprivation in the neighbourhood where the patient lived were associated with increased risk of clozapine discontinuation (HR = 2.12, 95% CI 1.30-3.47). Female gender (HR = 0.63, 95% CI 0.41-0.96) and clinical improvement after one month of treatment (HR = 0.56, 95% CI 0.44- 0.71) were significantly associated with a good response to clozapine. However, I found that up to six months of treatment may be required to determine non-response. This thesis implicates variants that may increase susceptibility to clozapine-associated neutropenia and contributes to our current understanding of the causes of clozapine discontinuation and treatment response.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General)