When it's more of a chore to watch than enjoyment.
Prison Break started losing it around season 3, I dropped it before 4. Likewise with Dexter.
I found the acting in Walking Dead kinda cringy, dropped it a few eps into season 2.
The only exception is with Lost. I wasn't even that into it and found it pretty stupid and boring with no direction around season 4-5, but I figured I had gone that far, so I stuck it out and finished it. Didn't really feel anything when people die later in the series, I was just going through the motions.