Background and hypothesis: Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS), yet the time course of clinical response in naturalistic settings is not well characterized. We hypothesized that patients initiated on clozapine in an outpatient clinic would demonstrate measurable symptom reduction over time, including delayed response in a subset of patients.
Study design: We conducted a retrospective study of TRS patients (N = 26) newly initiated on clozapine at an outpatient clozapine clinic. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and follow-up visits. Linear spline regression modeled PANSS trajectories over time. Response was defined as achieving either a ≥ 20% reduction in PANSS total score or a mild level of illness (PANSS score ≤ 58).
Study results: Patients demonstrated a mean 18.1-point reduction in PANSS total score during the first year of clozapine treatment, with significant improvements in positive and general psychopathology symptoms. Negative symptoms showed a modest, nonsignificant change. Overall, 20 patients (76.9%) achieved a ≥ 20% PANSS reduction, and 15 (57.7%) reached a mild symptom level. Six patients (23.1%) met response criteria only after 12 months of treatment.
Conclusions: In this naturalistic study, clozapine was associated with substantial symptom improvement, particularly within the first year. A subset of patients demonstrated delayed but clinically meaningful response, supporting the continued use of clozapine beyond 12 months. These findings underscore the value of sustained treatment in TRS.
Keywords: positive and negative syndrome scale; treatment-resistant; ultra treatment-resistant.
© The Author(s) 2025. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.