5. Jack (Subject Zero)
From: Mass Effect 2
Speaking of special individuals being used as lab rats until their brains are mush...
If you were to take River from Firefly, shave her head, replace her typical quirks with piracy, kidnapping, vandalism and murder, you'd have something that looks a lot like Jack (or Subject Zero, if you're so inclined). The biotic powerhouse was kept in a padded room by the sinister Cerberus group when she was a child, being psychologically tortured because why the hell not? They conditioned her to feel better when she killed people, turning murder into a drug of sorts. It made her stronger, gave her incredible powers and planted seeds of dissent that would eventually make her into one of the most dangerous criminals in the universe once she escaped. Yes, that's right, she escaped. Who thought that they could keep a psychic warrior in a cell?
She eventually joined Shepard's crew, asking him to return to the facility she was raised in so she could blow it up. It seemed like her mind was in a state of disrepair, but the more we interacted with her, the more we found that beneath her tough Girl, Interrupted exterior was a frightened, scared young woman, looking for closure after years of mental abuse.
Also, she wants really crazy, kinky sex... or creepy, sobby, crying sex. Either way, we're not going to judge.
4. Isaac Clarke
From: Dead Space series
Poor Isaac. In Dead Space, the engineer took a job to help rescue workers on the USG Ishimura, a planet-cracker ship that his girlfriend, Nicole, was stationed on. When he arrived, he was thrown into a conspiracy involving the Church of Unitology, Earth's government and zombie-like aliens called necromorphs, which need to be de-limbed in order to be killed. That, alone, could drive a man crazy, but those were the least of his worries – Isaac was also dealing with his own mind, which was slowly being turned against him by an artifact called The Marker. In the first game, it caused him to occasionally see a vision or two, but by the second game the marker's grip on Isaac was so strong that he was one lobotomy away from being smothered with a pillow by a towering Native American.
Clarke was having his sanity siphoned away by an alien artifact that caused lesser men to saw their own heads off with blades (in front of him, no less), and yet, somehow, he still carried on, doing his best to save humanity. We think. Or maybe the entire series has taken place within a padded cell. There's no way to know for sure.
Rumors are that Dead Space 3 will take Clarke's dementia to the next level, with even more visions tearing apart his fragile mind. Then again, after the things he's seen, it's hard to imagine that any hallucinations would actually be worse. He saw a guy drill a hole through his own eye. Seriously, what could be worse than that?
3. Sander Cohen
Honestly, just about every citizen of Rapture could fit on this list. From the woman pushing around a revolver in a baby carriage to the Splicers singing Jesus Loves Me, they're all a bunch of lovable damaged goods. But even within a city of insanity, one screwy, crazy son of a bitch stood out: Sander Cohen. Cohen is an artistic type that rules over Fort Frolic, the naughtiest part of Rapture, turning the crumbling city into one big, creepy art exhibit. He's put Splicers through all sorts of sadistic tortures, like forcing them to play the piano perfectly for fear of death if they mess up (and since they're sort of insane themselves, they usually mess up).
His most insane work of "art," however, was called the Quadtych. And to complete it, he required the player to take photographs of different corpses located around Fort Frolic and place them in the hands of dead bodies that have been covered in plaster to create statues. Once the Quadtych was complete, Cohen freaked the hell out and became paranoid that the player didn't appreciate the art. He sent waves of Splicers after the player while pumping Waltz of the Flowers from The Nutcracker over the speakers. Yeah. He's sort of a mess.
Once he calmed down, he actually came to see the art himself, rewarding the player before letting him leave. This made him one of the only characters in BioShock that we actually came face-to-face with and didn't have to kill. (We obviously killed him anyway, but the fact that we didn't have to is sort of awesome.)