I've been thinking about this alot myself recently, as I have a UCanDo3D that has some severe rudder coupling. I personally feel that the mix can be left on for any forward flight and normal (flying on the wing) aerobatic maneuvers, but I agree with OUTCAST that it can cause problems in high alpha maneuvers like a harrier, and also in a hover when all you want is a blast of prop wash to give you rudder pitch but with the mix on it also gives you a little unwanted elevator that you would have to correct.
This is my feeling for an airplane that has severe coupling issues, like the original question stated. If it were something more along the lines of say an Edge that doesn't couple very bad, I would leave it on all the time no matter the situation.