When I mixed it with Cthulu, my basic idea was this:
Change the Rules of Magic, then
Have Something Big Attack.
I decided to have magic make you go insane, and then pepper in giant tentacled horrors from beyond the stars, but it should work if you do something like...magic requires a sacrifice of life (one mortal per spell? ten mortals per spell?), or magic is defiling like Dark Sun, or magic suddenly goes wild, or spells open up the equivalent of nuclear explosions, or whatever.
Magic is sort of the way the good guys win in most of high fantasy including, especially, the Realms. Suddenly change the rules they work by, and problems get tough to solve.
Then you introduce not some falliable, intelligent, scheming villain, but simply something that's big and destructive. The Terrasque, or elementals, or a 4e-style demon, or Elder Gods.

The people of FR start to use magic to fight the thing -- and that magic does more harm.
I liked mixing the Mythos with FR because it helped me get that "helpless, horrified" feel that I feel works well as a counterpoint to most of FR's daisy-fresh fantasy. Elminster wasn't just killed off, and he didn't just go evil like a big cliche, but he went
insane, which is more dangerous. And then no one could find him, or any of the other powerful magical entities of the world (every Chosen? insane. Mystara herself? Insane. Divinations? Make you go insane), and had their own problems besides. A key part of the campaign revolved around infiltrating a horror-show perversion of the Dalelands, a sort of American Gothic filtered through HP Lovecraft, with terrible infinities and isolated, flesh-eating cannibal communities, trying to find the most powerful entity on the planet to beg him for help, only to find him knee-deep in his own waste babbling the Fibonacci sequence. "1, 1, 2, 3, 5..." That sort of iconic power reduced to helpless nothingness was much more effective than keeping him powerful and just making him a bad guy (and, of course, eventutally the PC's had to kill him, and it was poingiant and heart-wrenching to have to put down a world-famous hero, a sort of death of all the Realms were, rather than just a romp for haters -- when they put him down, it barely lasted three rounds).
Drizzit had his angsty rebellion removed since the drow, always paranoid and scared of their shadows at the best of times, faded into night-gaunts and then into simple vapor, the stuff of dreams. His own rebellion kept him grounded in the world for a little while longer, but he was struggling to hold on. When they searched the frozen north (because what is a Lovecraft-style game without at least one antarctic trip?), Drizzit was their guide, but was dangerous and unstable and eventually left them to die (and probably wandered off a cliff rather than become a spectre like the rest of the drow, at the end).
Things that I loved about that campaign:
- The people who loved FR had a lot of fun saving their favorite places and people. Once they knew that "magic = crazy town," they were able to make a big difference in the places they loved. I think one played an elf and loved the idea of Silverymoon, so I let her character actually make a difference there.
- The tone of hopelessness is a counterpoint to the FR tone of shiny good vs. stupid evil. Evil is no longer just "bad guys." You're fighting for simple survival against a force so overwhelming that it makes you crazy to contemplate it. PC's can be huge in such a setting, especially since magic doesn't solve any problems anymore.
- The flexibility that mystery gave me. I could have the players invested in various places without revealing events on the outside until the characters investigated, and found that the tide just keeps going, and more and more of the world is dark, and empty, and lonely, and dangerous.
If you want to keep it grounded in fantasy, I might set it
during the spellplague, rather than after. Mystara is dead, but everyone is still sorting out that event, as the spellplague begins to ravage various lands and alien monsters come from over the sea (the first people to see Dragonborn probably won't welcome them...). It would be a but more light-hearted, but it's still a pretty big RSE.
I also wouldn't have sold this as the "new Realms." I wouldn't play in the Realms after this. There's nothing really left. I would play in the realms during and before this, but the thing that's left is unrecognizable, drained of all the metaplot and characters that made people adore the Realms in the first place. If you never wanted the Realms in the first place, it's fine, but why would you call it a Realms game? If you wanted the Realms, this won't work, either.