Is the epidermal growth factor system a biomarker for clozapine response in schizophrenia?
Document TypePhD thesis
Access StatusThis item is embargoed and will be available on 2020-08-02.
© 2018 Dr. Sinnatamby Sujeevan
Schizophrenia is a severe neuropsychiatric disorder associated with significant disability. The antipsychotic drugs, the mainstay of treatment, are only effective in a proportion of patients. For those who do not respond, so-called treatment refractory schizophrenia (TRS) patients, the only available treatment is the atypical antipsychotic drug, clozapine. Although it has singular efficacy in treating TRS patients its use is restricted and delayed due to rare and potentially fatal side effects. Ability to predict response can help identify potential responders and introduce treatment early, but studies have so far not been able to identify any clinically useful biomarkers of response. A system that has been implicated in both schizophrenia and mechanism of action of clozapine is the epidermal growth factor (EGF) system. This study sought to examine the EGF system for potential predictors of response and did so by measuring peripheral EGF and betacellulin (BTC) levels in a prospective cohort of TRS patients commencing clozapine treatment. It also examined a larger cross-sectional sample of long-term clozapine treated patients for potential associations with EGF system single nucleotide polymorphisms (SNPs). The prospective sample of TRS patients were followed up over twenty-six weeks and clinical data and blood samples were collected at set time points. Symptom severity was measured using the Positive and Negative Syndrome Scale (PANSS). Additional clinical information was gathered using the Clinical Global Impression – Severity (CGI-S) scale, Global Assessment of Functioning (GAF) scale, Simpson Angus Scale (SAS) and the Calgary Depression Scale (CDS). Both EGF and BTC levels were determined using commercially available enzyme linked immuno-sorbent assay (ELISA) kits. Of the sixty-four patients who consented for the prospective study sixty entered the study and forty-nine completed the twenty-six weeks of clozapine treatment. Socio-demography of the patients revealed the significant disadvantages suffered by TRS patients. While 78.3% of the patients had completed more than ten years of education and 93.3% had been previously employed, at the time of the study 83.3% were dependent on the disability support pension. The average duration of illness of 11.2 years reflected the general reluctance and delay in introducing clozapine treatment. Although the response rate of 51.9% reiterated the unique efficacy of clozapine in treating TRS, the absence of any effect on negative symptoms highlighted this major gap in the treatment of schizophrenia. Significant improvement in both CGI-S and GAF scales in both responders and non-responders, while justifying continuation of treatment in the non-responders, also questions the current definition of response that is based solely on symptom improvement. Trends in smoking and psycho-active substance use, even though statistically not significant suggested possible additional advantages of clozapine. The low peripheral EGF and BTC levels in this study provide further support for an EGF system dysfunction in schizophrenia. Although clozapine treatment increased the EGF levels they still remained significantly lower than the healthy controls, implying that regardless of the duration of treatment, clozapine does not normalize EGF levels. Peripheral BTC levels were not affected by clozapine, but the correlation with positive symptoms suggest they could be a state marker. Neither EGF nor BTC levels predicted response to clozapine. The genetic analyses did not show any significant associations. Being an observational study, there was no provision to control for possible confounding factors, and having exclusively TRS patients limits its generalizability. Nevertheless, the findings of this study further implicate the EGF system both in schizophrenia and the mechanism of action of clozapine. Further exploration of this system would help better understand the pathogenesis of schizophrenia at the same time inform future development of antipsychotic medications.
Keywordsclozapine; treatment refractory schizophrenia; epidermal growth factor; betacellulin
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- Psychiatry - Theses