The role of psychosis and clozapine load in excessive checking in treatment-resistant schizophrenia

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Emilio, Fernandez-Egea 
Rudolf, Cardinal 
Trevor, Robbins 
Fernandez Egea, Emilio  ORCID logo

Background: A significant proportion of patients with clozapine-treated schizophrenia develop checking compulsions, a phenomenon yet to be understood. We use habit formation models developed in the cognitive neurosciences to conceptualise the complex relations between psychosis, clozapine action and compulsions.

Aims: The main research question investigated the dynamic interplay between psychosis, clozapine dose and obsessive– compulsive symptoms (OCS).

Method: Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classical bivariate correlation tests were used for assessing clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample.

Results: A total of 196 subjects and 459 face-to-face assessments were included. We found significant OCS to be common in clozapine-treated patients (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions [0.07 (Confidence interval 0.04, 0.09); p<0.001). No direct effect of psychosis on checking was identified [−0.28 (IC −0.09, 0.03); p=0.340]. After psychosis remission (n=65), checking compulsions correlated with both clozapine plasma levels (r=0.35; p=0.004) and dose (r=0.38; p=0.002). None of the glutamatergic and serotoninergic genetic variants found moderating the effect of psychosis on obsession and compulsion (SLC6A4, SCL1A1 and HTR2C) survived the multiple comparisons correction.

Conclusions: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians’ therapeutic decisions.

Journal Title
British Journal of Psychiatry
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Cambridge University Press
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MRC (MR/W029987/1)
An intramural research award from Universidad San Jorge supported ES. MB, IJB, and NS were supported by a studentship from the Mental Health Research UK. SC’s and RNC’s research was funded by the UK Medical Research Council (grant MC_PC_19213, MR/W014386/1). Dr. Fernandez-Egea is supported by the 2022 MRC/NIHR CARP award (MR/W029987/1), and this research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014, NIHR203312). The views expressed are those of the author(s) and not necessarily of the NIHR or the Department of Health and Social Care.