This is something I wouldn’t have really considered beforehand, but what Kaley Cuoco said does make a lot of sense.
Most sitcoms are filmed very differently from movies or even dramatic television shows, so there would need to be whole rhythm change when stepping onto set and working with a studio audience, whether it’s the first time, or just the first time in many years.
Unlike Bob Newhart (who’d starred in many seasons of his own sitcoms in the ’70s and ’80s), guest stars like Katee Sackhoff, LeVar Burton, Carrie Fisher, and James Earl Jones all either had very few or no stints on a sitcom before their brief time on The Big Bang Theory, so I can certainly see where, even though they were all great on the show, it probably took some getting used to.