Longitudinal course of cognition in schizophrenia: Does treatment resistance play a role?

Treatment-resistant schizophrenia (TRS) represents a main clinical issue, associated with worse functional outcome and higher healthcare costs. Clozapine is the most effective antipsychotic for TRS, although 40% of resistant patients, defined as ultra-treatment resistant (UTR), are clozapine-refractory. Previous literature suggests that TRS is characterized by worse cognitive functioning and a more disrupted neurobiological substrate, but only few studies focused on UTR schizophrenia. Moreover, despite this evidence and the central role of cognition, to date no study has investigated long-term cognitive outcome in TRS. Based on these premises, this study aims to analyze cross-sectional and long-term cognitive functioning of patients with schizophrenia, stratified according to antipsychotic response: first-line responders (FLRs), clozapine responders (CRs) and UTRs. We analyzed cross-sectional and retrospective cognitive evaluations of 93 patients with schizophrenia (32 FLRs, 42 CRs, 19 UTRs) over a mean follow-up period of 9 years, also taking into account possible influencing factors such as clinical severity and antipsychotic load. Analyses showed that UTR is associated with overall impaired cognitive functioning and represents the main predictor of long-term cognitive decline. We observed no significant differences between FLR and CR patients, which showed moderate cognitive improvement over time. This is the first study to report an association of treatment resistance with longitudinal cognitive course in schizophrenia, indicating that UTR is correlated with cognitive decline over time. This decline may either be a consequence of the persistence of psychotic symptoms or depend on a distinct and more disrupted neurobiological substrate affecting both cognition and antipsychotic response.