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

Abstract

Background: Severe mental illness (SMI; schizophrenia, bipolar disorders (BDs), and other nonorganic psychoses) is 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 findings: 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 30, 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 effects meta-analyses were conducted to compute pooled hazard ratios (HRs) and rate ratios, pooled standardised mortality ratios (SMRs), pooled odds ratios (ORs), and pooled risk ratios (RRs) 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 (NOS) score) were conducted. The narrative synthesis included 108 studies, and the quantitative synthesis 59 mortality studies (with (≥1,841,356 cases and 29,321,409 controls) and 28 incidence studies (≥401,909 cases and 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 results ranged from SMR = 1.55 (95% confidence interval (CI): 1.33 to 1.81, p < 0.001), for CVA in people with BD to HR/rate ratio = 2.40 (95% CI: 2.25 to 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 to 2.30, p = 0.71; 2000s: SMR = 2.59, 95% CI: 1.93 to 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 to 1.51, p = 0.016) for total CVD events to rate ratio 3.82 (95% CI: 3.1 to 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.

Conclusions: 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.

Fig 1. PRISMA flowchart.

CVD, cardiovascular disease; SMI, severe mental illness.

Fig 2. Forest plots showing relative risk of CVD mortality in those with versus without schizophrenia, studies included in meta-analysis.

Weights are from random effects model. Dashed lines show pooled estimated risks within subgroups. Studies were allocated to decades according to the median year of follow-up. CHD, coronary heart disease; CVA, cerebrovascular accident; CVD, all circulatory disease; F, female; HR, hazard ratio; M, male; OR, odds ratio; SCZ, schizophrenia; SMR, standardised mortality ratio.

Fig 3. Forest plots showing relative risk of CVD mortality in those with versus without BD, studies included in meta-analysis.

Weights are from random effects model. Dashed lines show pooled estimated risks within subgroups. Studies were allocated to decades according to the median year of follow-up. BD, bipolar disorder; CHD, coronary heart disease; CVA, cerebrovascular accident; CVD, all circulatory disease; F, female; HR, hazard ratio; M, male; OR, odds ratio; SMR, standardised mortality ratio.

Fig 4. Trend in risk of CVD mortality for SMI compared with control participants, by median decade.

BD, bipolar disorder; CHD, coronary heart disease; CI, confidence interval; CVA, cerebrovascular accident; CVD, all circulatory disease; HR, hazard ratio; RRatio, rate ratio; SMI, severe mental illness; SMR, standardised mortality ratio; SCZ, schizophrenia. The year 1970 includes studies with median between 1950 and 1970. y-Axes show estimated risks on log scale, and shaded areas show 95% CIs for risk estimates.

Fig 5. Trend in risk of CVD incidence for SMI compared with control participants, by median decade.

BD, bipolar disorder; CHD, coronary heart disease; CI, confidence interval; CVA, cerebrovascular accident; CVD, major cardiovascular events; HR, hazard ratio; OR, odds ratio; RR, risk ratio; RRatio, rate ratio; SCZ, schizophrenia; SMI, severe mental illness. y-Axes show estimated risks on log scale, and shaded areas show 95% CIs for risk estimates.