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

  • Parita Shah
  • Yusuke Iwata
  • Eric E. Brown
  • Julia Kim
  • Marcos Sanches
  • Hiroyoshi Takeuchi
  • Shinichiro Nakajima
  • Margaret Hahn
  • Gary Remington
  • Philip Gerretsen
  • Ariel Graff-GuerreroEmail author
Original Paper


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 χ2 = 5.33, p = 0.021) and number of pre-clozapine hospitalizations (OR = 0.95, Wald χ2 = 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.


Clozaril Treatment Psychosis Schizophrenia Outcome Response 



Funding for this study was provided by the Ontario Mental Health Foundation (Type A grant) and the Canadian Institutes of Health Research (MOP-142493 and MOP-141968). We are grateful to Wanna Mar, Research Coordinator, for providing administrative support. We also thank research volunteers Danielle Uy, Katharine Constable, Kathryn Kalahani-Bargis, and Kristy Orser for their assistance with organizing the study data for analysis.

Compliance with ethical standards

Conflict of interest

PS reports no conflict of interest. YI reports receiving fellowship grants from Keio University Medical Science Foundation, Mitsukoshi Foundation, Japan Foundation for Aging and Health, and manuscript fees from Dainippon Sumitomo Pharma. EEB reports no conflict of interest. JK and MS report no conflict of interest. HT has received speaker’s honoraria from Meiji-Seika Pharma, Mochida, Otsuka, Sumitomo Dainippon Pharma, and Yoshitomi Yakuhin and manuscript fees from Sumitomo Dainippon Pharma. SN has received fellowship grants from Canadian Institute of Health Research (CIHR), research support from Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, Daiichi Sankyo, and manuscript fees or speaker’s honoraria from Dainippon Sumitomo Pharma and Yoshitomi Yakuhin within the past three years. MH reports being on an advisory board for Alkermes in the past. GR reports external funding from CIHR, travel support from Neurocrine Biosciences, and research support from HLS. PG reports receiving research support from the CIHR, Ontario Ministry of Health and Long-Term Care, Ontario Mental Health Foundation (OMHF), and the Centre for Addiction and Mental Health (CAMH). AGG reports receiving support from the United States National Institute of Health, CIHR, OMHF, Consejo Nacional de Ciencia y Tecnología, the Instituto de Ciencia y Tecnología del DF, the Brain & Behavior Research Foundation (Formerly NARSAD), the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation Early Research Award, and Janssen.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Parita Shah
    • 1
    • 2
  • Yusuke Iwata
    • 1
    • 3
  • Eric E. Brown
    • 1
    • 2
    • 3
    • 4
  • Julia Kim
    • 1
    • 2
  • Marcos Sanches
    • 6
    • 7
  • Hiroyoshi Takeuchi
    • 9
  • Shinichiro Nakajima
    • 1
    • 9
  • Margaret Hahn
    • 2
    • 3
    • 5
    • 8
  • Gary Remington
    • 2
    • 3
    • 4
    • 5
  • Philip Gerretsen
    • 1
    • 2
    • 3
    • 4
    • 5
  • Ariel Graff-Guerrero
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  1. 1.Multimodal Imaging Group, Research Imaging CentreCentre for Addiction and Mental Health (CAMH)TorontoCanada
  2. 2.Institute of Medical ScienceUniversity of TorontoTorontoCanada
  3. 3.Department of PsychiatryUniversity of TorontoTorontoCanada
  4. 4.Geriatric Mental Health Division, CAMHUniversity of TorontoTorontoCanada
  5. 5.Campbell Family Mental Health Research Institute, CAMHUniversity of TorontoTorontoCanada
  6. 6.Krembil Centre for Neuroinformatics, CAMHTorontoCanada
  7. 7.Biostatistics Department, Dalla Lana School of Public HealthUniversity of TorontoTorontoCanada
  8. 8.Banting and Best Diabetes CentreUniversity of TorontoTorontoCanada
  9. 9.Department of Neuropsychiatry, School of MedicineKeio UniversityTokyoJapan

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