Are you primarily worried about heating or air conditioning? What you don't want is your return positioned so it can suck your supply in before it ends up being distributed around the room. Where are the supply ducts, in the ceiling or low near the floor?
FWIW, I find that in my home, pulling the hot air out from the ceiling, whether heating or cooling, and running the fan on low gives me the most even room temperature. A/c ducts at the floor aren't the greatest, nor are heating ducts in the ceiling. They both can be made to work if carefully positioned and you have good returns and your fan is up to it.