-->PONE-D-25-54201-->-->Rising Trends in Antipsychotic-Associated Mortality: The Role of Deprivation, Ethnicity, and Regional Disparities-->-->PLOS One

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Reviewer #1: Jan 21, 2026

Peer review report

Dear Editor,

Thank you for the opportunity to review this manuscript titled “Rising Trends in Antipsychotic-Associated Mortality: The Role of Deprivation, Ethnicity, and Regional Disparities.”

I first present my summary of what I understood after carefully reading through the manuscript, then I provide my detailed comments.

Summary:

This is a population-based analysis of national data in England. Prescription data were obtained from the NHS Business Services Authority (NHSBSA), and mortality data were obtained from the UK Office for National Statistics (ONS). The authors examine the association between antipsychotic prescriptions and “antipsychotic-related mortality.” Unfortunately, the authors define antipsychotic-related mortality as “records of deaths where an antipsychotic was mentioned on the death certificate,” and it is unclear what this represents. It is not clear whether this reflects antipsychotic poisoning (as the authors mention elsewhere) or mortality in people prescribed antipsychotics, which is not the same as antipsychotic-associated mortality and would undermine the results of this analysis.

The authors then analyze the relationship between mortality and antipsychotic prescriptions across NHS England regions, as well as ethnic and deprivation factors (income, employment, education, and health). The authors analyze data from 2015 to 2023 and conclude that average antipsychotic-related mortality per million prescriptions has increased over the past decade, with the increase mostly in more urbanized regions (for example London). The Midlands, however, show a significantly decreasing rate, and the abstract does not report this accurately. In addition, the authors do not report the change in prescribing patterns which is important in interpreting the results.

The main issue I have with this work is the definition of antipsychotic-associated mortality as any death certificate where an antipsychotic is mentioned. This pragmatic definition is not defended, not clearly detailed, and risks overestimating antipsychotic-associated mortality. It also makes it difficult to interpret regional and deprivation effects as “antipsychotic-associated mortality.” Another major issue is the lack of other variables that can explain mortality patterns, such as age, sex, and chronic medical illness.

I believe the title, abstract, and main text need to be revised to clearly convey what the authors actually analyzed. If the outcome is closer to “mortality in people prescribed antipsychotics,” this should be stated explicitly and consistently. If the outcome is antipsychotic poisoning, then the methods and outcome definition need to match this claim. In addition, key sociodemographic variables that determine mortality need to be included to clarify the relationship between prescriptions and mortality. The discussion should be expanded to fully explore strengths and limitations.

Detailed comments:

A. Introduction

1. In the first paragraph, the authors correctly note the established efficacy of antipsychotics in severe mental illness. They cite one study in schizophrenia. I suggest adding more studies on the efficacy of antipsychotics in severe mental illness to strengthen the introduction:

10.1016/S0140-6736(19)31135-3

10.1016/j.eclinm.2022.101690

10.1097/MD.0000000000034670

2. In addition to established efficacy in treating symptoms, antipsychotics have been associated with reduced mortality in schizophrenia in some population-based studies, for example:

10.1016/j.euroneuro.2025.112745

10.1016/S2215-0366(25)00268-8

This is important to acknowledge in the introduction, and to address in the discussion, especially given the side effect burden and the increase in mortality suggested by this manuscript and other work.

3. I suggest the authors paraphrase the sentence: “Adverse outcomes associated with antipsychotics include extrapyramidal symptoms (first-generation antipsychotics), metabolic complications (second-generation antipsychotics) and severe events such as poisoning and death” to: “Adverse outcomes associated with antipsychotics include drug-induced movement disorders, metabolic dysfunction, and severe events such as toxicity and death.”

I make this suggestion because movement disorders still occur with second-generation agents, and metabolic dysfunction is not exclusive to a single class.

B. Methods

1. The authors need to justify why Asian ethnicity was used as a predictor in the data analysis plan (including prior literature or preliminary analysis).

2. The authors need to provide more details on what they mean by “an antipsychotic was mentioned on the death certificate.” The names of agents considered antipsychotics need to be listed (perhaps in the supplementary), how this was extracted needs to be described, and whether this can be replicated needs to be clear. The justification for using this pragmatic approach to define “antipsychotic-associated mortality” should be explicitly stated. If this definition cannot be defended as antipsychotic-associated mortality, then the outcome should be renamed to be more accurate. My suggestion is “mortality in people prescribed antipsychotics,” if that is what the data represents.

3. Related to the previous point, the methods mention "antipsychotic poisoning" elsewhere which is a completely different clinical diagnosis and this needs to be clarified.

C. Results

1. The authors report:

“The linear regression analysis at the national level showed a statistically significant positive coefficient, indicating an increasing upward trend (p < 0.01) (Table S2 and Figure 1).” Given that mortality is defined as death certificates in which an antipsychotic is mentioned, the authors also need to report whether prescription counts increased during these years.

2. The regional analysis showed significant disparities. These results indicate decreasing rates over time in the Midlands. This suggests that factors other than prescriptions may be driving the rising association with mortality at the national level. It also means the abstract needs revision. In the abstract, the authors state: “the lowest in the Midlands,” but do not state clearly that this is a decrease. I suggest revising the abstract to explicitly state a significant decrease in the Midlands.

3. The authors report models including deprivation and Asian ethnicity, but do not include other major determinants of mortality such as age and sex. Given that these factors could be major contributors to mortality in people prescribed antipsychotics, and not the prescription itself, this limits the interpretability of the results.

4. The authors briefly mention that the association between mortality rates and deprivation was non-linear, but do not explain that this could reflect other unexplored variables.

5. Figure labels need revision. For example, “Linear analysis of Asian and deprivation with antipsychotic death rates” is unclear as Asian is not a directly quantifiable variable. If the model uses proportion of Asian residents, this should be stated.

D. Discussion and conclusions

1. The authors might want to discuss in detail the possibility that increased mortality associated with antipsychotics may relate, in addition to systemic factors, to overprescription or inappropriate use in populations for whom efficacy and safety has not been established.

2. One strength of the approach is using deaths per million prescriptions, which partially accounts for increases in prescriptions over time. This should be stated explicitly in the discussion as a strength, while still acknowledging the limitations of the mortality definition.

3. The analysis of trends before and after COVID-19 is a main strength.

4. Including all deaths where an antipsychotic is mentioned on the death certificate creates a major limitation and risks overestimating harm. This needs to be clearly stated in the limitations.

5. Another important point is reverse causation. It is possible that antipsychotics are increasingly prescribed in sicker populations with higher baseline mortality, which would increase the association between antipsychotics and mortality. For example, it is possible that clinicians are treating patients with schizophrenia more frequently with antipsychotics, and schizophrenia is associated with increased mortality, and therefore the trend shows increasing mortality in people prescribed antipsychotics. This possibility needs to be clearly stated.

6. I believe the conclusions are overstated given the outcome definition and the lack of key mortality determinants in the models and also given that regional findings include a significant decrease in the Midlands. The possibility of reverse causation and overestimation of mortality are major limitations.

Thank you once again for the opportunity to review this manuscript.

Reviewer #2: This study addresses an important public health issue by analyzing national-level data on antipsychotic-associated mortality in England over nearly a decade. The findings regarding the rising mortality rate and its association with regional deprivation and ethnic density are compelling and suggest a need for targeted clinical and policy interventions. However, the manuscript requires further clarification on its methodology and a more nuanced interpretation of the findings, particularly regarding the potential confounding factors inherent in population-level ecological studies.

1. The authors define mortality based on the mention of an antipsychotic on the death certificate, but it remains unclear whether these deaths were primarily due to acute toxicity such as poisoning or chronic physical complications like cardiovascular events associated with long-term use; therefore, please clarify if the ONS data used distinguish between "deaths due to drug poisoning" and "deaths where antipsychotics were a contributing factor," and discuss how this distinction relates to the overall increased mortality trends described in the study.

2. While the study uses prescription item counts as a denominator to evaluate mortality rates, regional variations in these outcomes might reflect differences in the underlying prevalence and severity of mental illnesses rather than the pharmacological effects of the medications themselves; consequently, the authors should discuss how regional disparities in the prevalence of severe mental illness might confound the observed association between deprivation and mortality.

3. To move beyond simple association and better address potential causality, it is necessary for the authors to provide more granular data—if available—regarding the specific causes of death associated with different classes of antipsychotics (e.g., first-generation vs. second-generation); this would allow for a more robust discussion on whether the increased mortality is driven by acute pharmacological toxicity, metabolic complications, or systemic inequalities in the monitoring of high-risk patients.

Reviewer #3: Introduction:

• Recommend removing the specifiers of first generation antipsychotics with extrapyramidal symptoms and second generation antipsychotics with metabolic complications as agents in both classes can cause both types of adverse effects (even if they are more prominent in one class vs. the other)

• You correctly state that there is inconclusive evidence on the effect of antipsychotics on mortality, but the objective in your abstract clearly states that antipsychotics are associated with increased mortality. This must be rectified.

• Please define “deprivation”- as a reader from outside of the UK I am not familiar with this term being used in the context of socioeconomic disadvantage and it was not clear to me whether you were referring to individuals lacking a specific resource.

• Please elaborate on the idea of ethnicity being protective against psychoses- how would this influence antipsychotic-related mortality?

• Please elaborate on how prescribing patterns influence mortality and how understanding disparities can influence prescribing patterns to improve outcomes. If the links between these concepts were more clearly laid out and/or the scope was more narrowly defined, that could strengthen the generalizability of your study.

Methods:

• Can you do an analysis comparing the change in mortality rate over time stratified by the different regions/ethnic/socioeconomic groups? I am curious if the overall trend is driven by any particular subgroup.

Discussion:

• You state that “a cautious and personalised approach to treatment should be encouraged, considering the adverse effects and variation in prescribing and cultural beliefs and practices.” Can you provide a specific example to better illustrate this point? Or reference literature that describes this type of approach in a tangible way that clinicians reading your paper may be able to incorporate into their practice?

• The claim that your study “emphasises the importance of personalised treatment in managing patients on antipsychotic medications” may be a bit of a leap for a population-level analysis, which as you mentioned in the limitations does not include individual patient data or control for confounding.

Figures 3 and 4:

• Please clarify the axis labels for these graphs with units.

Overall:

• The abstract and introduction must be fair and balanced when setting the stage for an investigation on the effects of antipsychotic medications on mortality. There is evidence for these agents both increasing and decreasing mortality, so both must be presented in an objective way.

• I think it is important to note that your study only included outpatients, which tend to be a less severe population. This should be discussed in terms of the effect on generalizability of your findings.

• I came away unsure what you hypothesized was causing antipsychotic-related mortality to increase over time. You suggest the use of high doses in older patients but don’t share any evidence to support this practice is becoming more common. It seems like the opposite trend would be expected since our knowledge of monitoring for and identifying adverse effects has improved over time and the agents that have come on the market in the last 10 years have all generally had more favorable metabolic profiles and/or been LAIs.

• Your conclusions focus on the importance of considering patient characteristics such as geographic region, socioeconomic status, and ethnicity rather than exploring the reasons behind the observed increase in antipsychotic-related mortality over time. I believe a meaningful way to tie these concepts together is to analyze the effects of region/deprivation/ethnicity on the rate of change in antipsychotic-related mortality over time to determine the relative impact of each of these variables. It seems like the ultimate goal should be to reduce the mortality rate associated with antipsychotics and if we had some clues as to what is driving the rate increase it would helpful for developing mitigation strategies. Deprescribing and the use of non-pharmacological therapy aren’t strategies to reduce the rate of antipsychotic-related mortality per prescription.

• You conclude that regional differences in prescribing patterns contribute to disparities, but at the population level it is impossible to attribute the observed regional differences to prescribing patterns specifically. You also mention access to resources as a regional variable. It would be more accurate to state that you observed regional difference and not speculate at the driving force.

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Reviewer #3: Yes: Shaina Schwartz

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-->PONE-D-25-54201R1-->-->Rising Trends in Deaths involving Antipsychotics: The Role of Deprivation, Ethnicity, and Regional Disparities-->-->PLOS One

Dear Dr. Khan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jun 06 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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-->

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We look forward to receiving your revised manuscript.

Kind regards,

Hikaru Hori

Academic Editor

PLOS One

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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Reviewer #1: I would like to thank the authors for addressing my comments.

The manuscript has improved significantly, and now clarifies the outcome "Deaths involving Antipsychotics" and specifies how that outcome was operationalized.

Thank you

Reviewer #2: As the authors adequately revised the manuscript according to the reviewers' comments, I have no further comments and think that the current version is now acceptable.

Reviewer #3: Thank you for providing revisions to your manuscript. The remaining comments I have are:

1) I still think more could be done to establish the link between ethnic density and antipsychotic mortality. You cited literature about ethnic density protecting against psychosis but not how this translates to reduced antipsychotic-related mortality. Can you provide any evidence to support better cardiovascular and/or metabolic health in these areas that could counteract the adverse events seen with antipsychotics? If you are attributing the protective effect to "better engagement with healthcare services" then please expand on how specifically this could reduce antipsychotic mortality. You do not have to state a claim, just hypothesize as to what might be driving your finding.

2) You do a nice job discussing potential mechanisms underlying antipsychotic mortality, but I am still left to wonder why it is increasing over time. You brought up dosing- do you have evidence that dosing is increasing over time? Does this in any way explain the regional differences you observed? Same a above, you do not have to state a claim but hypothesize as to what might underly your main finding.

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Reviewer #1: Yes: Mohammed A. Alarabi

Reviewer #2: No

Reviewer #3: Yes: Shaina Schwartz

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-->

Trends in Recorded Deaths involving Antipsychotics: The Role of Deprivation, Ethnicity, and Regional Disparities

PONE-D-25-54201R2

Dear Dr. Khan,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Hikaru Hori

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PLOS One

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Reviewer #3: All comments have been addressed

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Reviewer #3: Yes

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Reviewer #3: I Don't Know

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Reviewer #3: Yes

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Reviewer #3: Thank you for responding to my comments and submitting revisions. I have no further recommendations.

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Reviewer #3: Yes: Shaina Schwartz

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