Background: Motivational deficits are a central feature of the negative syndrome in schizophrenia. They have consistently been associated with reduced willingness to expend physical effort in return for monetary rewards on effort based decision making (EBDM) paradigms. Nevertheless, the mechanisms underlying such altered performance are not well characterised, and it remains unclear if they are driven purely by negative symptoms, or also in part by cognitive impairment, antipsychotic treatment or even positive symptoms. Here we investigated the impact of all these factors using a paradigm that has not previously been used to measure EBDM in schizophrenia. Methods: Forty treatment resistant schizophrenia (TRS) patients on clozapine and matched controls (N = 80) completed a well validated EBDM task which offers monetary rewards in return for physical effort. Choice and reaction time data was analysed using logistic regressions, as well as Bayesian hierarchical drift diffusion modelling (HDDM). Behavioural parameters were compared between groups and their association with negative symptoms, cognitive function and serum clozapine levels were assessed. Results: Overall, TRS patients were significantly less motivated than controls during effort-based decision making. They demonstrated reduced sensitivity to increasing rewards, but surprisingly were also less averse to increasing effort. Despite a positive correlation between negative symptoms and cognitive function in TRS, reward sensitivity was associated only with cognitive performance. In contrast, reduced effort aversion correlated with negative symptom severity. Clozapine levels and positive symptoms were not associated with either behavioural parameter. Conclusion: Motivational deficits in TRS are characterised by both diminished reward sensitivity and reduced effort aversion during EBDM. Cognitive dysfunction and negative symptom severity account for distinct aspects of these behavioural changes, despite positive associations between themselves. Overall, these findings demonstrate that negative symptoms and cognitive impairment have significant independent contributions to EBDM in TRS, thereby opening the possibility of individualised treatment targeting these mechanisms to improve motivation.

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.