¹Newcastle University, Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom, ²Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust (CNTW), Regional Affective Disorders Service (RADS), Newcastle upon Tyne, United Kingdom, ³University of Oxford, Department of Experimental Psychology, Oxford, United Kingdom, ⁴Manchester University NHS Foundation Trust, Manchester University, Manchester, United Kingdom, ⁵Newcastle University, Population Health Sciences Institute, Newcastle upon Tyne, United Kingdom, ⁶Newcastle University, Biosciences Institute, Newcastle upon Tyne, United Kingdom

Background: Depression is associated with increased mortality. Uncertainty remains on the underlying causes.

Aims & Objectives: Depression with physical co-morbidity is associated with increased mortality. This systematic review and meta-analysis examined cardiovascular (CV) mortality in depression and how comorbidities and antidepressant treatments modify this.

Method: We searched Medline, Embase, Scopus, Web of Science and Cochrane registers (inception to 31 December 2024) for randomized controlled trials (RCTs) and observational studies comparing CV mortality in adults with depression vs without, and receiving antidepressants vs controls. We excluded studies with <12 months follow-up, reporting only all-cause mortality or lacking control groups. Random-effects meta-analyses were conducted with CV mortality as the primary outcome. Risk of bias was assessed with RoB 2 and ROBINS-I. PROSPERO: CRD42020200812.

Results: We included 7 RCTs and 47 cohort studies (1,593,722 people). In multivariable-adjusted cohorts (k=26), depression was associated with a significantly higher CV mortality versus no-depression (hazard ratio [HR] 1.45, 95%CI 1.25-1.69). Effects were similar in non-selected community-dwelling cohorts and those with CV disease or type 2 diabetes. Antidepressants overall were associated with increased CV mortality in cohorts but after adjustment only tricyclic antidepressants (TCAs) had significantly increased risk vs no antidepressant (k=4; HR 1.27, 95%CI 1.02-1.58). RCT findings were directionally consistent but underpowered.

Discussion & Conclusions: Depression is associated with increased risk of CV mortality irrespective of comorbid group studied. Antidepressants do not appear to modify this risk, apart from TCAs, which may increase it. The antidepressant models in particular had high heterogeneity, reflecting a knowledge gap on the long-term effects of antidepressants in patients with depression on CV mortality.