Often in such fanfictions, the plot may involve a betrayal that pushes Harry over the edge. It could be a friend or a mentor who turns on him. This sudden shift in loyalty would shatter his world view. He has always relied on the support of those around him, and when that is taken away, it becomes difficult for him to stay sane. His actions would then become erratic as he struggles to come to terms with this new and cruel reality.
Obviously, Harry Potter himself is the central character. Since the story is about him losing his sanity, he is at the core of the plot. Then there would likely be his friends like Hermione and Ron. Their reactions to Harry's deteriorating mental state would be important aspects of the story. They might try to help him, or they could be at a loss about what to do.
Maybe Orochimaru manages to get his hands on Naruto and subjects him to some dark and twisted experiments. These experiments could mess with Naruto's mind, causing him to lose his sanity. He could start seeing illusions all the time, believing his friends are his enemies. As a result, he'd be in a constant state of confusion and aggression, and his once - positive attitude towards life and ninja - hood would be completely gone.
It could be Kaguya. If Kaguya were to return and use her powerful abilities to drive Naruto mad, perhaps by invading his mind with dark thoughts and memories. She has the power to warp reality and minds, so she could easily make Naruto lose his sanity. And since she has a grudge against the world of ninjas, making Naruto, one of the most powerful ninjas, go insane would be a great way for her to start her reign of terror all over again.
It could be that Naruto discovers some dark secrets about his past, like his parents were actually killed by the very people he trusted in the village. This revelation is so shocking that it shatters his mental state. He becomes a completely different person, losing his sense of right and wrong, and his sanity along with it.
One possible plot could be that Naruto's loss of sanity causes him to have a distorted view of the Fem Kyuubi. Maybe he sees her as both a threat and a source of power he can't control. This could lead to a conflict within himself as he battles his inner demons while also interacting with the Fem Kyuubi in unexpected ways. For example, instead of the usual relationship of cooperation or taming, he might try to completely dominate her, which would be a big shift from the normal Naruto we know.
Perhaps an unknown and powerful dark ninja. This ninja could be from a long - forgotten clan with dark powers. They might have a vendetta against the Leaf Village and see Naruto as the key to their revenge. So they use their dark arts to make Naruto lose his sanity and turn him against his own village.
Other characters in the Naruto universe might also be affected. For example, his friends like Sakura and Kakashi would notice the change in Naruto. They might try to help him, but their attempts could be in vain because of the complex situation with the Fem Kyuubi involved. This would create new tensions and storylines as they struggle to deal with a Naruto who has lost his sanity and the mystery of the Fem Kyuubi's role in it.
It could be Voldemort. Voldemort might use Harry's love as a weapon against him. He could either kill her or turn her against Harry. Another possibility is Draco Malfoy. Maybe Draco tricks Harry's love into thinking he's a better choice. Or it could be a new, unknown dark wizard who targets Harry through his love.
His friends, Hermione and Ron, would surely help. Hermione with her intelligence and Ron with his loyalty.
Harry might maintain his sanity through his memories of Hogwarts. The thought of his friends, the magic he has learned, and the happy times at school could be his mental refuge. For example, he could recall the fun times in Potions class or flying on his broomstick during Quidditch matches.