Clozapine Augmentation Strategies and Clinical Predictors of Prolonged Tertiary Hospitalization in Clozapine-Resistant Schizophrenia: a Retrospective Cohort Study.
6 affiliations
- 1Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, V6T1Z3, Canada.
- 2Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T2A1, Canada.
- 3BC Psychosis Program, Vancouver, British Columbia, V6T2A1, Canada.
- 4Machine Learning Engineer based in San Francisco, San Francisco, CA, United States.
- 5Non-Invasive Neurostimulation Therapies Laboratory, Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T2A1, Canada.
- 6School of Biomedical Engineering, Faculty of Applied Science | Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T1Z3, Canada.
Abstract
Background and hypothesis
Clozapine-resistant schizophrenia (CRS) remains a major clinical challenge, with persistent symptoms and functional impairment despite adequate clozapine treatment. Real-world evidence is limited, and guidelines recommend a narrow set of augmentation strategies-aripiprazole (D2/3R partial agonist), amisulpride (D2/3R selective antagonist), and electroconvulsive therapy (ECT)-without clear guidance on selection or sequencing. This study examined augmentation choice and its association with length of stay (LOS) and symptomatic outcomes.Study design
We conducted a retrospective cohort study using BC Psychosis Program electronic records (2012-2025). Symptom severity and functioning scores (PANSS, CGI-S, GAPS, SOFAS) were extracted at admission and discharge. Multivariable Cox models assessed LOS for index and discharge augmentation strategies. ANCOVA compared symptom change across discharge strategies. A machine-learning model examined predictors of ECT versus pharmacological augmentation at discharge.Study results
Eighty-eight admissions were included. In adjusted index models, D2/3R selective antagonism was associated with shorter LOS than ECT (HR 2.50, 95% CI 1.35-4.62); partial agonism was not (HR 1.41, 95% CI 0.75-2.63). Partial agonist augmentation had the highest inefficacy-related switching. By discharge strategy, ECT was associated with greater reduction in positive symptoms than selective antagonism (MD -3.20, 95% CI -5.65 to -0.75) and partial agonism (MD -3.87, 95% CI -6.57 to -1.16). Greater impairment in psychosis and functioning on admission predicted ECT at discharge (AUC 0.74; balanced accuracy 0.72).Conclusions
D2/3R selective antagonism was the most resource-efficient strategy, while ECT produced greater improvement in positive symptoms. Incorporating baseline psychosis severity and functioning into measurement-based care may support more informed augmentation selection.
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BibTeX
@article{baldwin2026clozapine,
title = {{Clozapine Augmentation Strategies and Clinical Predictors of Prolonged Tertiary Hospitalization in Clozapine-Resistant Schizophrenia: a Retrospective Cohort Study.}},
author = {Kaitlyn Baldwin and William G Honer and Reza Shahbazi and Diane Fredrikson and Randall F White and Fidel Villa-Rodriguez and Reza Rafizadeh},
journal = {Schizophrenia bulletin},
year = {2026},
month = oct,
doi = {10.1093/schbul/sbag187},
url = {https://europepmc.org/article/MED/42951688},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Clozapine Augmentation Strategies and Clinical Predictors of Prolonged Tertiary Hospitalization in Clozapine-Resistant Schizophrenia: a Retrospective Cohort Study.
AU - Kaitlyn Baldwin
AU - William G Honer
AU - Reza Shahbazi
AU - Diane Fredrikson
AU - Randall F White
AU - Fidel Villa-Rodriguez
AU - Reza Rafizadeh
PY - 2026
DA - 2026/10/01
JO - Schizophrenia bulletin
DO - 10.1093/schbul/sbag187
UR - https://europepmc.org/article/MED/42951688
AB - Background and hypothesis Clozapine-resistant schizophrenia (CRS) remains a major clinical challenge, with persistent symptoms and functional impairment despite adequate clozapine treatment. Real-world evidence is limited, and guidelines recommend a narrow set of augmentation strategies-aripiprazole (D2/3R partial agonist), amisulpride (D2/3R selective antagonist), and electroconvulsive therapy (ECT)-without clear guidance on selection or sequencing. This study examined augmentation choice and its association with length of stay (LOS) and symptomatic outcomes.Study design We conducted a retrospective cohort study using BC Psychosis Program electronic records (2012-2025). Symptom severity and functioning scores (PANSS, CGI-S, GAPS, SOFAS) were extracted at admission and discharge. Multivariable Cox models assessed LOS for index and discharge augmentation strategies. ANCOVA compared symptom change across discharge strategies. A machine-learning model examined predictors of ECT versus pharmacological augmentation at discharge.Study results Eighty-eight admissions were included. In adjusted index models, D2/3R selective antagonism was associated with shorter LOS than ECT (HR 2.50, 95% CI 1.35-4.62); partial agonism was not (HR 1.41, 95% CI 0.75-2.63). Partial agonist augmentation had the highest inefficacy-related switching. By discharge strategy, ECT was associated with greater reduction in positive symptoms than selective antagonism (MD -3.20, 95% CI -5.65 to -0.75) and partial agonism (MD -3.87, 95% CI -6.57 to -1.16). Greater impairment in psychosis and functioning on admission predicted ECT at discharge (AUC 0.74; balanced accuracy 0.72).Conclusions D2/3R selective antagonism was the most resource-efficient strategy, while ECT produced greater improvement in positive symptoms. Incorporating baseline psychosis severity and functioning into measurement-based care may support more informed augmentation selection.
SN - 1787-9965
SN - 1745-1701
SN - 0586-7614
ER -