Hi everyone!
I'm an old fan of Planescape, trying to set up a new campaign using Pandemonium as basis.
My starting background is:
Everyone knows that listening to the winds of Pandemonium will make you go nuts. But if you can really listen, among the howling and the maddening sounds, you can hear feeble and eerie whispers. And these whispers can be a source of secret and forbidden knowledge. This was well know by the Arlians, an humanoid race living in Cocytus. Actually, they are the ones carving all the forgotten tunnels now are crumbling to dust in that layer. The Arlians were able to "filter" the maddening sounds and thoughts carried from the winds and to keep only the secret whispers (are these whispers coming from another world, passing from the Source?? who knows....). Thanks to this particular source of knowledge, they were extravagant geniuses, strange artists, wise men (but in a very peculiar way of course), but pacific and devoted only to the search for knowledge. Of course they were in good term with the Bleakers, Xaositect and even the Godsmen.
But the most evil inhabitants of Pandemonium wasn't happy about these pacific and too much neutral wise men. So Loki tricked Ekelor, a demi-god, the only warrior among the Arlian pantheon, to defeat the evil source of the winds, located somewhere in the deep of Agathion or beyond. Loki was thinking that sooner or later, in this impossible quest, Ekelor would have been defeated by some terrible creature there (the Arlians were not renowned for their combat skill), leaving its people without any more defence. Ekelor started to march toward the deepest part of the plane, but going closer and closer to the Source of the winds, he got stronger and stronger listening to the whispers, at the price of losing its mind totally. He emerged from his quest as a crazy and avenging god, able to put in chain Loki, and then rampaging in the Outlands in a war against everyone there, considered now "enemy" of Arlia. Do you have in mind Hulk?
He started to move to the "right" direction of the great wheel, going directly to Glorium and Ysgard (well, Loki could have been happy about this), and it was backed by tanar'ri forces eager to have a part in this senseless slaughter. Some of the Arlians, particularly his personal clergy and worshippers, followed him, driven crazy in an "empathic" way, even if most of the Arlians stayed in their town trying to stop this madness with the power of their belief. The force of Law and Good decided to unite against this powerful foe: they rallied some troops and war erupted. From Glorium, Ekelor was forced to retreat back to Pandemonium, but many of the devas and lesser deities died as well. When the war reached Pandemonium, well, the situation got out of hand. The devas was tainted from the howling winds, the Arlians considered them in danger and tried to organize a self defence, the Blood War forces came to slaughter everyone. The result: Ekelor was not able to be killed but only confined in a layer deeper than Agathion and the Arlians were massacred by devas and fiends alike. The few survivors of the Arlians enclosed theirselves in the capital, shutting any contact with the outside and keeping with their force of will Ekelor in a deep slumber.
Today, a couple of millennia later. A friend of the PCs is an archaeologist and he retrieved some old artefacts depicting Ekelor (a statuette, a votive shield....). Secret agents of the Arlians, specialized to this kind of operations, come and rob everything: they want to be forgotten by everyone. The PCs will try to track them down in Sigil and beyond, starting to reveal some secrets of this forgotten civilization. Eventually they will find the lost capital in Cocytus, ally with them and try to kill once for all the poor crazy Ekelor.
I'll try to have a lot of strange adventures, based on amnesia, dreams and strange change of settings, to keep up the "crazy" side. I had some inspiration by your adventure hooks, like the Sensory stone trap and the Groundhog day. Any else? 
What I am also missing it's a good villain (a *good villain* is always essential for me!). I was wondering on someone wishing to repeat the original quest of Ekelor because he believes he can become strong as him without getting crazy. So this guy will try to put his hands (or claws) on the Arlian artefacts and knowledge before the PC. Obviously, at the end he will get just plain crazy. A high-up of which factions can be particularly fit to this role? Maybe Mercykillers want just to kill Ekelor and all the Arlians to punish them (but they can be interested in his power), maybe the Harmonium want to cover all the traces of the past slaughter made by the devas, maybe some of the *chaotic* sided factions want to free him and unleash some chaos. In any case, the secret agendas of the factions will be likely in conflict with the "oblivion" and neutrality agenda of the Arlians.
The most important long term free will choices of the PCs during the campaign are which side support (their Factions or the Arlians, or trying to get a compromise), and how to confront Ekelor at the end (just releasing him from his madness or trying to get some power from him).
Thanks everyone to any suggestions!!!
This may not fit in too well; but in my campaign, I had a new sect/faction I called the Caretakers of the Mind. To all outward appearances, they were concerned with caring for and healing the mad. (I took the Gatehouse Asylum from the Bleakers - leaving them the soup kitchens - and gave the madhouse over to the Caretakers)
Side note: one of the nicknames for this group were the "Inmates" (as in "the inmates are running the asylum)
But unknown to most, the Caretakers believed that the mad held some key to a deeper, almost incomprehensible, knowledge of the planes. They were secretly studying the insane, experimenting on them and sometimes even inducing madness in the sane in their attempts to get to this knowledge.
While I don't think this will fill the niche of main villain that you seem to be searching for, they might make good rivals (maybe even occassional allies) if they also get wind of Ekelor and his power. Think of them as the Nazis in "Raiders of the Lost Ark" who are racing to the same goal as the heroes with dire consequences if they get there first.
The PCs might also find resistance as most people in Sigil view the Caretakers as good-hearted souls that are trying to help the ill. The PCs claims of twisted experiments performed by the Caretakers would earn them disapproving looks and suspicions that they have gone mad in Pandemonium.