39 The immunomodulatory effect of clozapine in patients with treatment resistant schizophrenia: a retrospective cohort study

Abstract

Objectives The pathoetiology of Schizophrenia remains elusive, however, a growing body of literature suggests immune dysfunction may contribute. Clozapine, an atypical antipsychotic, has superior efficacy in treatment-resistant Schizophrenia compared to other antipsychotics – however underlying mechanisms remain unknown. Clozapine has recognised immunomodulatory effects, responsible for potentially fatal haematological side-effects - such as agranulocytosis. Whether Clozapine’s immunomodulatory properties contribute toward its unique efficacy in treatment-resistant schizophrenia has not been systematically explored. Methods A retrospective cohort study design was employed to examine the relationship between white cell, neutrophil, and platelet temporal trajectories and Clozapine response in treatment-resistant schizophrenia. Eligible patients were initiated on Clozapine for the first time and continued treatment for at least twelve weeks between 2007 and 2014 within the South London and Maudsley NHS Foundation Trust, and underwent weekly haematological monitoring. Retrospective clinical ratings were performed at baseline and three months following initiation, based upon patients’ electronic clinical notes accessed through the Maudsley BRC Clinical Records Interactive Search system. Treatment response was defined as ‘much’ or ‘very much’ improved on the Clinical Global Impression – Improvement subscale. Serial cell counts were extracted from a Clozapine haematological monitoring database. Results Of 188 included patients, 114 (61%) responded to treatment. Response did not significantly vary by ethnicity or age. Mean interval between haematological assessments was 6.9 (SD 2.0) days. General linear models revealed a significant increase from baseline for all cell lines in the second treatment week (p=0.001) which persisted for three weeks (p=0.001). Group based trajectory modelling indicated that 15% of patients showed a temporary increase in white cell and neutrophil trajectories. Logistic regression revealed that treatment response was not associated with a ‘spike’ in cell count. However, females were 2.08 times more likely to respond to treatment (95% CI [1.09, 4.08], p=0.017) and 2.67 times more likely to exhibit a ‘spike’ in cell counts following Clozapine initiation (95% CI [1.14, 6.24], p=0.023). Conclusions This is the first study to examine whether Clozapine’s immunomodulatory properties contribute towards its unique efficacy. We found that clozapine was associated with an early ‘spike’ in all cell lines. Further analysis revealed a relatively small portion of patients were responsible for this transient increase. Increased cell counts did not predict Clozapine response at three months, but gender was implicated as a potential moderator variable.