Temporal trends in associations between severe mental illness and risk of cardiovascular disease: A systematic review and meta-analysis

Amanda M Lambert, Helen M Parretti, Emma Pearce, Malcolm J Price, Mark Riley, Ronan Ryan, Natalie Tyldesley-marshall, Tuba Saygın Avşar, Gemma Matthewman, Alexandra Lee, Khaled Ahmed, Maria Lisa Odland, Christoph U. Correll, Marco Solmi, Tom Marshall

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Severe mental illness (SMI) (schizophrenia, bipolar disorders (BD), and other non-organic psychoses) are associated with increased risk of cardiovascular disease (CVD) and CVD-related mortality. To date, no systematic review has investigated changes in population level CVD-related mortality over calendar time. It is unclear if this relationship has changed over time in higher-income countries with changing treatments.
Methods and results
To address this gap, a systematic review was conducted, to assess the association between SMI and CVD including temporal change. Seven databases were searched (last: November 30th, 2021), for cohort or case-control studies lasting ≥1 year, comparing frequency of CVD mortality or incidence in high-income countries between people with, versus without SMI. No language restrictions were applied. Random-effect meta-analyses were conducted to compute pooled hazard ratios (HRs) and rate ratios, pooled standardized mortality ratios (SMRs), pooled odds ratios, and pooled risk ratios of CVD in those with versus without SMI. Temporal trends were explored by decade. Subgroup analyses by age, sex, setting, world region, and study quality (Newcastle-Ottawa scale score) were conducted.
The narrative synthesis included 108 studies; the quantitative synthesis 59 mortality studies (with (>1,841,356 cases, 29,321,409 controls) and 28 incidence studies (>401,909 cases, 14,372,146 controls). The risk of CVD-related mortality for people with SMI was higher than controls across most comparisons, except for total CVD-related mortality for BD and cerebrovascular accident (CVA) for mixed SMI. Estimated risks were larger for schizophrenia than BD. Pooled SMRs ranged from 1.55 (95% CI: 1.33-1.81, p<0.001), for CVA in people with BD to 2.40 (95% CI: 2.25-2.55, p<0.001) for CVA in schizophrenia.
For schizophrenia and BD, SMRs and pooled HRs/rate ratios for CHD and CVD mortality were larger in studies with outcomes occurring during the 1990s and 2000s than earlier decades (1980s: SMR=1.14, 95% CI: 0.57-2.30, p=0.710; 2000s: SMR=2.59, 95% CI: 1.93-3.47, p<0.001 for schizophrenia and CHD) and in studies including people with younger age.
The incidence of CVA, CVD events and heart failure in SMI was higher than controls. Estimated risks for schizophrenia ranged from HR/rate ratio 1.25 (95% CI: 1.04-1.51, p=0.016) for total CVD events to rate ratio 3.82 (95% CI: 3.1-4.71, p<0.001) for heart failure. Incidence of CHD was higher in BD versus controls. However, for schizophrenia CHD was elevated in higher quality studies only. The HR/rate ratios for CVA and CHD were larger in studies with outcomes occurring after the 1990s.
Study limitations include the high risk of bias of some studies as they drew a comparison cohort from general population rates and the fact that it was difficult to exclude studies that had overlapping populations, although attempts were made to minimise this.
In this study we found that SMI was associated with an approximate doubling in the rate ratio of CVD-related mortality, particularly since the 1990s, and in younger groups. SMI was also associated with increased incidence of CVA and CHD relative to control participants since the 1990s. More research is needed to clarify the association between SMI and CHD and ways to mitigate this risk.
Original languageEnglish
Article numbere1003960
Number of pages32
JournalPLoS Medicine
Issue number4
Publication statusPublished - 19 Apr 2022

Bibliographical note

Funding Information:
This report presents independent research funded by the National Institute for Health and Care Research (NIHR). AML and TM are supported by the NIHR Applied Research Collaboration (ARC) West Midlands. HMP (NIHR Academic Clinical Lectureship) was funded by the NIHR during some of this research. MJP was supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank Danai Bem for screening titles and abstracts and providing guidance and critical appraisal during the development of the protocol and the review process and Arwa Abdel-Aal for help with piloting the title and abstract screening used in this systematic review.

Publisher Copyright:
Copyright: © 2022 Lambert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


  • Cardiovascular Diseases/epidemiology
  • Heart Failure
  • Humans
  • Mental Disorders/complications
  • Psychotic Disorders
  • Schizophrenia/complications


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