This study investigates the bidirectional causality between mental disorders, antidepressant use, and cardiovascular disease (CVD). Using Mendelian randomization (MR) and multivariable MR (MVMR) analyses, the researchers examined the causal links between 10 mental disorders, antidepressant use, and 7 types of CVD. The findings indicate that major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and insomnia are associated with increased risks of multiple CVDs. Additionally, antidepressant use is linked to heightened risks of each CVD, including arrhythmias, atrial fibrillation, coronary artery disease (CAD), hypertension, heart failure (HF), stroke, and overall CVD. However, MDD itself was not found to be associated with an increased risk of any CVD. The study highlights the independent risk factor role of antidepressants in CVD and suggests that the influence of MDD on CVD may be mediated by the use of antidepressants. These findings have important clinical implications for the treatment of patients with antidepressants, emphasizing the need to consider both the beneficial and detrimental effects of these medications.This study investigates the bidirectional causality between mental disorders, antidepressant use, and cardiovascular disease (CVD). Using Mendelian randomization (MR) and multivariable MR (MVMR) analyses, the researchers examined the causal links between 10 mental disorders, antidepressant use, and 7 types of CVD. The findings indicate that major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and insomnia are associated with increased risks of multiple CVDs. Additionally, antidepressant use is linked to heightened risks of each CVD, including arrhythmias, atrial fibrillation, coronary artery disease (CAD), hypertension, heart failure (HF), stroke, and overall CVD. However, MDD itself was not found to be associated with an increased risk of any CVD. The study highlights the independent risk factor role of antidepressants in CVD and suggests that the influence of MDD on CVD may be mediated by the use of antidepressants. These findings have important clinical implications for the treatment of patients with antidepressants, emphasizing the need to consider both the beneficial and detrimental effects of these medications.