Given the varying distribution of PDE5 across organs, recent research has extensively explored the potential therapeutic effect of sildenafil in various other conditions, such as pain, cancer, Alzheimer’s disease, depression, Raynaud’s phenomenon, digital ulcers, wound healing, retinopathy, gastric ulcer, colitis, nephropathy, lung injuries, and ischaemia, providing novel potential clinical applications for this molecule. This evidence concerns the gene PDE5A and depressive disorder.