Francesca Kingston1*
Robert Stewart1,2
Risha Govind1Amelia Jewell1
Vishal Bhavsar1,3†
James H. MacCabe4†- 1Maudsley Biomedical Research Centre (BRC), South London and Maudsley National Health Service (NHS) Foundation Trust, London, United Kingdom
- 2Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- 3Section of Women’s Mental Health, The David Goldberg Centre for Health Services and Population Research, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- 4Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
People with schizophrenia experience violent victimization, and interventions to reduce this risk are needed. We tested the association of clozapine treatment with risk of exposure to assault and head injuries using electronic health records linked to a national clozapine treatment register and to national hospitalization data. The unadjusted incidence rate ratio (IRR) for clozapine treatment on exposure to assault and head injuries was 0.44 (95% confidence interval [CI]: 0.28-0.69). This effect remained statistically significant after covariate adjustment (0.46 (0.29-0.74); 0.40 (0.22-0.71) in men; 0.64 (0.29-1.43) in women. Clozapine treatment was thus associated with a substantially reduced risk of exposure to assault and head injuries.
1 Introduction
There is increased research attention toward patient safety in severe mental illness (SMI), considering the prevalence of victimization, its impacts, and its absence from routine psychiatric assessment (1). Victimization is associated with more severe symptomatology, lack of social support, and repeat victimization (1).
Clozapine is an atypical antipsychotic associated with reduced symptoms and hospitalization in schizophrenia (2). Despite this, clozapine is considered under-prescribed, due to concerns surrounding rare health risks. A study using national registers found clozapine was associated with the lowest relative risk of any crime of all antipsychotics (3). A mirror-image study from our group showed that clozapine initiation is associated with reduced violent crime in the following 2 years compared to the previous 2 years, and this effect is stronger for clozapine than olanzapine (4). However, despite research examining the association of clozapine with perpetration of violence, there is limited research on the association of clozapine treatment with the risk of being subject to violent victimization. Therefore, we tested the association between clozapine treatment and exposure to assaults, traumatic brain injuries, and head injuries in an electronic health records database for a large NHS mental health trust in Southeast London, linked to a register of clozapine treatment and national hospitalization data.
2 Methods
2.1 Data sources
We analyzed de-identified patient data from the South London and Maudsley (SLaM) NHS Trust, which is made available for secondary analysis via the Clinical Record Interactive Search (CRIS) system (5). CRIS has ethical approval for use in secondary analysis (5) from Research Ethics Committee, Oxford C (reference 23/SC/0257). Patients in CRIS were linked to the Zaponex Treatment Access System (ZTAS), the provider of mandatory blood monitoring for clozapine-treatment SLaM patients, as part of previous work (6). In brief, clozapine treatment periods (with start and end dates) were estimated from full blood count test date information held within ZTAS. We excluded patients with missing age and primary diagnosis data.
2.2 Measurements
Clozapine treatment periods were measured by operationalizing start dates as falling when a patient received their first clozapine blood test, or when the blood test was labelled as a baseline measurement, or when the blood test was conducted after an interval of between 35 and 60 days from the previous blood test, based on an algorithm developed in previous clozapine research by a member of the team (6). Clozapine treatment end dates were operationalized as falling when a patient received their final test, or when the test was associated with a red result (i.e., white blood cell count < 3.0 x 109/L and/or neutrophil count < 1.5 x 109/L), or when the treatment status accompanying the test was set to ‘discontinued’, ‘interrupted’, or ‘transferred’. Off-treatment periods were defined as the times between consecutive treatment periods. Dates of exposure to assault and head injury were collected using hospital episode statistics data (7), linked to CRIS (8), for admissions to acute medical hospitals where the discharge diagnosis included ICD-10 diagnostic codes for assault (X85-X99, Y00-Y09), head injury (S00-S09), or traumatic brain injury (S02.0, S02.1, S02.3, S02.7-S02.9, S06.0-S06.9, S07.1). Given small cell sizes for individual assault and head injury outcomes, which cannot be reported separately due to restrictions on CRIS data, all outcome categories (assault, TBI, and AHI) were collapsed into one category, referred to as “assaults and head injuries” which is presented in counts.
2.3 Analysis
Stata 17 was used for all analyses. To test the research objective, episodes of clozapine treatment were compared with episodes without treatment in zero-inflated Poisson regressions (estimating incidence rate ratios, IRRs), taking account of clustering of treatment episodes within patients using the Stata “cluster” command. Estimates for men and women were estimated by including a multiplicative interaction term in the final model and then calculating fitted estimates by linear combination. Age (grouped for reporting into the bands: < 16, 16 – 24, 25 – 34, 35 – 44, 45 – 54, 55+), gender, ethnicity (White, Black, Asian, Mixed, Other), and marital status (single, married/cohabiting, divorced/separated, widowed) were collected at referral from structured EHR fields. Substance use diagnosis, and any inpatient psychiatric admission, within the first year following referral were measured using structured fields. Information on aggression, and antipsychotic exposure were collected using natural language algorithms applied to the first year of clinical notes data.
3 Results
Table 1 describes patient sociodemographic characteristics and zero-inflated Poisson model estimates accounting for clustering of treatment episodes within patients. There were 1,345 patients in the study. Prevalence of injuries increased with age, from 3.1% in 16–24-year-olds, to 34.3% in those aged 55 and older. The prevalence of assault and head injury events, expressed as counts, during follow up was similar between male and females (11.9% and 10% respectively). White patients had the highest prevalence of assault and head injury incidents during follow up (15%).
Table 1. Description of patient data analysed in this study, and model estimates (incidence rate ratios, IRR, with 95% confidence intervals in parentheses) from zero-inflated Poisson models, for association of clozapine treatment with the rate of any assault and head injury, and gender-stratified estimates.
The unadjusted IRR for the association between clozapine treatment and rates of any assault and head injury was 0.44 (95% confidence interval [CI]: 0.28, 0.69). This effect remained similar in magnitude after adjustment for covariates (IRR = 0.46, 95% CI: 0.29, 0.74). Gender-stratified analyses indicated an adjusted IRR of 0.40 (0.22, 0.71) for men, and 0.64 (0.29, 1.43) for women. We did not find statistical evidence for interaction by gender.
4 Discussion
We found a reduced rate of exposure to assault and head injury experienced by patients when they were on clozapine treatment, compared to periods when they were off clozapine treatment. This rate reduction was greater in magnitude for male patients than for female patients, although we did not find statistical evidence for interaction by gender.
To our knowledge, our study is the first to investigate the association between clozapine treatment exposure and the rate of exposure to assault and head injury incidents. We studied a sample of a patients from a large NHS mental health provider, with available information on periods of clozapine treatment taken from linked ZTAS data. Nevertheless, the final sample size was 1345, limiting precision of our estimates. Our measurement of exposure to assault and head injury incidents was based hospitalization data which is a widely used measure of population violence exposure but is likely to be an underestimate of all incidents of violent injury to which patients may have been exposed.
As blood monitoring is a mandatory condition of clozapine treatment, clozapine-prescribed patients can experience greater contact with services, potentially conferring additional therapeutic effects to the group studied. Previous research has not found clinical contact to account for the negative association between clozapine use and mortality, after adjusting models for inpatient and outpatient clinical contact (9).
We used date information from national mandatory blood monitoring system to compute clozapine treatment start and end dates. This may have introduced inaccuracy. We were unable to measure non-clozapine antipsychotic prescribing in the study population, which is likely to have been variable between on and off clozapine periods, potentially introducing bias into our results. Future research should consider the possible impact of antipsychotic prescribing on exposure to violent injury with detail on treatment periods across a range of antipsychotic drugs.
Clozapine is associated with a range of beneficial effects in people diagnosed with schizophrenia. Clozapine has previously shown to be associated with reduced self-harming behavior and lower mortality (10), and reduced perpetration of violence (4). Our findings suggest that clozapine treatment could be associated with reduced exposure to assault and head injury in patients with schizophrenia. Future research should examine this relationship in larger study populations with detailed information on prescribing. This evidence could be relevant to clinical discussions about the risks and benefits of clozapine treatment and guide personalized management of patients with schizophrenia.
Data availability statement
The data analyzed in this study is subject to the following licenses/restrictions: No new data was created in this study. The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants. Research material availability is not applicable to this article as no new materials were used in this study. The analytic code supporting the findings of this study is not available to other researchers via a recognized repository, but can be made available on request from author VB. . Requests to access these datasets should be directed to Vishal Bhavsar, dmlzaGFsLjIuYmhhdnNhckBrY2wuYWMudWs=.
Ethics statement
The studies involving humans were approved by Research Ethics Committee, Oxford C (reference 23/SC/0257). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.
Author contributions
FK: Conceptualization, Formal Analysis, Writing – original draft, Writing – review & editing. RS: Supervision, Writing – original draft, Writing – review & editing. RG: Conceptualization, Data curation, Supervision, Writing – original draft, Writing – review & editing. AJ: Supervision, Writing – original draft, Writing – review & editing. VB: Conceptualization, Data curation, Formal Analysis, Methodology, Supervision, Writing – original draft, Writing – review & editing. JM: Conceptualization, Formal Analysis, Methodology, Supervision, Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health award to South London and Maudsley NHS Foundation Trust (SLaM) and the Institute of Psychiatry at King’s College London (KCL). VB is funded by an NIHR Advanced Fellowship in health services research (NIHR302243). RS and JM are part-funded by the NIHR Maudsley Biomedical Research Centre at SLaM and KCL. RS is also part-funded by (i) the NIHR Applied Research Collaboration South London (NIHR ARC South London) at King’s College Hospital NHS Foundation Trust; (ii) UKRI – Medical Research Council through the DATAMIND HDR UK Mental Health Data Hub (MRC reference: MR/W014386); (iii) the UK Prevention Research Partnership (Violence, Health and Society; MR-VO49879/1), an initiative funded by UK Research and Innovation Councils, the Department of Health and Social Care (England) and the UK devolved administrations, and leading health research charities.
Conflict of interest
RS declares research support received within the last 3 years from GSK and Takeda.
The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Walsh E, Moran P, Scott C, McKenzie K, Burns T, Creed F, et al. UK700 Group. Prevalence of violent victimisation in severe mental illness. Br J Psychiatry. (2003) :183:233–8. doi: 10.1192/bjp.183.3.233
2. Wagner E, Siafis S, Fernando P, Falkai P, Honer WG, Röh A, et al. Efficacy and safety of clozapine in psychotic disorders—a systematic quantitative meta-review. Trans Psychiatry. (2021) 11:487. doi: 10.1038/s41398-021-01613-2
3. Sariaslan A, Leucht S, Zetterqvist J, Lichtenstein P, and Fazel S. Associations between individual antipsychotics and the risk of arrests and convictions of violent and other crime: a nationwide within-individual study of 74–925 persons. psychol Med. (2022) 52:3792–800. doi: 10.1017/S0033291721000556
4. Bhavsar V, Kosidou K, Widman L, Orsini N, Hodsoll J, Dalman C, et al. Clozapine treatment and offending: a within-subject study of patients with psychotic disorders in Sweden. Schizophr bulletin. (2020) 46:303–10. doi: 10.1093/schbul/sbz055
5. Stewart R, Soremekun M, Perera G, Broadbent M, Callard F, Denis M, et al. The South London and Maudsley NHS foundation trust biomedical research centre (SLAM BRC) case register: development and descriptive data. BMC Psychiatry. (2009) 9:51. doi: 10.1186/1471-244X-9-51
6. Govind R, Jewell A, Whiskey E, Gee S, Oloyede E, Taylor D, et al. Frequency of neutropenia over time in patients on clozapine. medRxiv. (2022). doi: 10.1101/2022.01.25.22269860
7. Wijlaars L, Herbert A, Zylbersztejn A, Hardelid P, and Cromwell D. Data resource profile: hospital episode statistics admitted patient care (HES APC). Int J Epidemiol. (2017) 46:1093. doi: 10.1093/ije/dyx015
8. Perera G, Broadbent M, Callard F, Chang C-K, Downs J, Dutta R, et al. Cohort profile of the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) case register: current status and recent enhancement of an electronic mental health record-derived data resource. BMJ Open. (2016) 6:e008721. doi: 10.1136/bmjopen-2015-008721
9. Hayes RD, Downs J, Chang C-K, Jackson RG, Shetty H, Broadbent M, et al. The effect of clozapine on premature mortality: an assessment of clinical monitoring and other potential confounders. Schizophr Bull. (2015) 41:644–55. doi: 10.1093/schbul/sbu120
Keywords: antipsychotic, clozapine, cohort, head injury, schizophrenia, victimization
Citation: Kingston F, Stewart R, Govind R, Jewell A, Bhavsar V and MacCabe JH (2026) The association of clozapine treatment periods with incidence of exposure to assault and head injuries - a cohort study of electronic health records. Front. Psychiatry 16:1704073. doi: 10.3389/fpsyt.2025.1704073
Received: 12 September 2025; Accepted: 24 December 2025; Revised: 22 December 2025;
Published: 21 January 2026.
Edited by:
Giorgio Di Lorenzo, University of Rome Tor Vergata, ItalyReviewed by:
Koji Takeda, National Center of Neurology and Psychiatry, JapanJustin Faden, Rowan University School of Osteopathic Medicine, United States
Copyright © 2026 Kingston, Stewart, Govind, Jewell, Bhavsar and MacCabe. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Francesca Kingston, ZmtpbmdzdG9uQHNsYW0ubmhzLnVr
†These authors share senior authorship