Depression, ischaemic heart disease and cerebrovascular disease are important causes of morbidity and are among the leading contributors to global health burden. These conditions often occur in the same patient, resulting in considerably greater effect on health than combinations of chronic diseases without depression. The frequent occurrence of these conditions in the same patient raises the possibility of a common genetic predisposition, similar risk factors or a pathophysiological link. Serotoninergic and adrenergic signalling play important roles in causing major depression and also in platelet activation and aggregation, which underlies vascular disease. This review discusses the potential pathophysiological link between major depression and conditions in which platelet activation plays an important role and also provides evidence linking the use of the most commonly used antidepressant drugs (i.e. the selective serotonin re-uptake inhibitors) to increased risk of bleeding.