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Still being caught in depression over the disruption of his last self-written project, The Man Who Killed Don Quixote, his constant struggle with the established studio system, as well as becoming aware of his progressing age, worried that he was going nowhere with his latest projects and that he might not have much time left, Gilliam put a number of references to sudden, tragic, and premature death into his script before the loss of Ledger became a reality. In fact, Gilliam felt compelled to emphasize time and again that upon the film's release many things might be mistaken as references to Ledger's fate but that the script wasn't changed apart from re-casting Tony with Depp, Farrell, and Law.
Gilliam felt that "[I] didn't make this film. Forces from above and below made it. It made itself. I don't worry anymore. It's got its own relentless momentum. It just needed some human sacrifice." "It's made itself - I was just one pair of hands and there were many hands." "Don't get me into my mystical mode ... but the film made itself and it was co-directed by Heath Ledger!" "The irony is that the choices that were forced upon us improved the movie, so it was as if Heath co-directed the movie, even co-wrote it."
Gilliam said in retrospect about the first transition from Ledger to Depp in the film:
"He's extraordinary. That's why I put Johnny in first position [of the three new Tonys], because number one, he was going to be the most difficult to get any time with, and number two, I just thought if it works with the transition to Johnny and if the audience goes for it, they'll follow the next two. And that's exactly how it works. [...] That's what's funny, when Johnny appears so many people think it's Heath! And it's a trick: Johnny's not doing anything. He looks like Johnny. [...]
"[During the initial shoot] Heath was on stage and the Russians are appearing, and he was behaving in a very funny way, he was moving around, and I said, 'Heath, I know what you're doing.' He said, 'What are you talking about?' 'You're doing Johnny Depp, aren't you?' And can you believe, that helps this transition [when Ledger enters the mirror and becomes Depp]. This was not intended!"
Gilliam and McKeown based the character of Tony on former British prime minister Tony Blair, who "would say the most insane things and probably he'd believe them himself".
Initially, Tom Cruise expressed interest in being involved as another actor to replace Ledger, but Gilliam turned him down because Cruise had never been a close friend of Ledger.