Clozapine response trajectories and predictors of non-response in treatment-resistant schizophrenia: a chart review study

Although clozapine is the main antipsychotic medication for treatment-resistant schizophrenia, 40-70% of patients on clozapine have persistent psychotic symptoms (i.e. ultra-treatment-resistant schizophrenia, UTRS). We aimed to examine clozapine response/non-response patterns in patients with treatment-resistant schizophrenia, as well as determine patient clinico-demographic factors associated with long-term clozapine non-response. Clinico-demographic characteristics of 241 patients on clozapine were collected through a retrospective chart review. The median (interquartile range, IQR) follow-up from illness onset was 25.0 (IQR = 24.0) years. Clozapine response was assessed at median 10.8 (IQR = 14.0) months (Time 1, T1) and 7.2 (IQR = 13.5) years (Time 2, T2) after its initiation. It was evaluated by chart reviewers based on the information provided in clinical notes. Binomial logistic regression was used to determine clinico-demographic factors associated with clozapine non-response at both T1 and T2 (i.e. stable UTRS, S-UTRS) compared to clozapine response at both times (i.e. stable clozapine responders, S-ClozResp). Among clozapine responders (n = 122) at T1, 83.6% remained clozapine responsive and 16.4% became non-responsive at T2. In the UTRS group (n = 119) at T1, 87.4% remained clozapine non-responsive and 12.6% became responsive at T2. Duration of delay in clozapine initiation (OR = 0.94, Wald chi(2) = 5.33, p = 0.021) and number of pre-clozapine hospitalizations (OR = 0.95, Wald chi(2) = 5.20, p = 0.023) were associated with S-UTRS. Most UTRS patients were non-responsive to clozapine from the start of treatment. Preventing delay in initiating clozapine and relapses could help promote long-term clozapine response in patients with treatment-resistant schizophrenia. Future longitudinal studies are required to explore the neuropathological correlates of relapses and delay in clozapine initiation.