Phenomenology and genetic moderators of excessive checking after antipsychotic treatment

A significant proportion of antipsychotic-treated schizophrenia patients develop de novo checking compulsions, a phenomenon that is yet to be understood. Informed by models of habit formation developed in the cognitive neurosciences, we hypothesised that excessive checking could be understood as the by-product of psychosis, promoted by clozapine’s strong anti-serotoninergic action. Using the anonymised electronic records of a cohort of 204 clozapine-treated patients, including longitudinal assessments of obsessive-compulsive symptoms (OCS) and psychosis (n=724 face-to-face assessments), we performed longitudinal multi-level mediation and multi-level moderation analyses to explore OCS’ associations with psychosis and with patient genotype respectively. We found OCS to be common in clozapine-treated patients (54%), with checking being the most prevalent symptom. Mediation models showed psychosis severity to indirectly effect checking behaviour by inducing obsessions [0.08 (IC 0.05, 0.12); p<0.001). No direct effect of psychosis on checking was identified [-0.06 (IC -0.13, 0.02); p=0.145]. After psychosis remission, checking compulsion directly correlated with both clozapine plasma levels (r=0.33; p=0.005) and dose (r=0.30; p=0.010). The transition from psychosis to obsession and compulsion was moderated by glutamatergic genetic variants (GRIN2B). We also identified novel associations with the serotoninergic pathway (SLC6A4, HTR2A and HTR2C). Understanding the different phases of the complex transition from psychosis to compulsion may inform clinicians' therapeutic decisions.