As far as theories goes, i believe if DPC wants to add very dark stuff to the game without resorting on death he will make Neil get very, very sick... maybe on the lines of cancer and other stuff.
And MC would have to deal with his rock, the pillar he based his whole life around, cracking and tumbling and slowly coming down. This can lead to very dark stuff that characters like Vinny can take advantage of and if MC had contact with drugs he can even decent in some heavy usage.
This for me would be ideal way of making the game take a dark turn without killing someone... and if someone has to die it would be:
1. Helen, due to her disease.
2. Mick, due to being a minor character that is a mole for a secondary character that is an antagonist of sorts.
3. Patrick?, this one is more wild and even darker. Since imo he would end himself after Helen dies and having nowhere to support himself, it can heavily depend on some choices and even Maya and Derek's reactions.