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According to co-creator Trey Parker, the episode "Raisins" (in which Stan's girlfriend Wendy breaks up with him) was based on the trials and tribulations he went through when he found his fiancée in bed with another man. Stan's thoughts in the episode reflect Parker's.
The character of Cartman's mom was created and named after Parker's ex-fiancée who left him at the altar. Liane Cartman has slept with virtually every inhabitant of South Park, although as of late she's actually become more firm and less slutty, indicating that Parker's feelings on the matter have died down at this point.
The same girlfriend was the name of the horse in Cannibal The Musical — who leaves Parker's character during the film. In fact, just listen to the drunken commentary on the DVD.
At a convention, Meghan McCarthy said of writing My Little Pony: Friendship Is Magic that the reason that one of the main characters goes crazy in many of the episodes she's written is because they were mostly composed in the wee hours of the morning under a tight deadline, reflecting her stress.
Shortly after the first season of Rocko's Modern Life Joe Murray's first wife committed suicide, so Murray started spending less and less time working on the series, until he finally just gave up on it altogether. Thus seasons 3 and 4 are not produced by him, and the series came to an end after season 4. For a while out of grief, he Mis-blamed the series for his wife's suicide.
A similar turn of events happened with Camp Lazlo, this time a result of his second wife divorcing him.
Towards the end of his theatrical career Tex Avery suffered from depression and was convinced that he couldn't be funny anymore.
Skyler Page, creator of Clarence, had problems with bipolar disorder that, combined with the stress of running a show, caused a psychotic episode where he groped female co-workers and ran out into the street shirtless yelling at police officers, speaking in different characters voices, riddles and They Might Be Giants songs. His disorder having caused some trouble in the past, as well as the sexual harassment incidents becoming public and creating a PR panic, led to him being fired by Cartoon Network and the role of Clarence being recast.
The breakdown actually came way before that. He tried smoking cigarettes with his nose, charging into the street shirtless while screaming at cops, drinking olive juice, staying up for days, answering questions with riddles, and when going to a mental hospital after the event he began to sing They Might Be Giants songs while strapped to a hospital bed.
Narrowly averted with Pendleton Ward, who stepped down as showrunner for Adventure Time sometime during the production of season five, after realizing that the stress of running the show was starting to drive him crazy.