It wasn't instantaneous. It wasn't even noticeable at first. It happened gradually over time, but Penny had broken his heart. That fateful encounter in which she steered him toward another woman was the catalyst for his emotional downward spiral, until he was a mere shell of a once-formidable Home Novus.
He still had his work. His colleagues may not respect him as a person - and lately he could not blame them, for he barely respected himself - but they respected his work. It was what kept him sane through his troubles. His first loves, science fiction and science fact, would always be there to welcome him home and comfort him after a long day of traversing the minefield that was Amy Farrah Fowler's romanticism.
His work and hobbies could only go so far, however, and indeed Amy was not as clever as she thought if she hadn't yet deduced that Sheldon had figured out her so-called "5 year plan."
It and she were starting to wear on his patience and restraint. But this wasn't about Amy Farrah Fowler. This was about Penny.
Penny had broken his heart and led him, knowingly or not, onto the path of melancholy and weakness he now tread.
He was reaching a turning point soon, he could feel it coming, as though he were remembering a dream from which he had long since awakened. He imagined it was another reality pressing close, wearing thin, showing him the possibilities.
Every time he tried to leave, Penny tried to keep him. Every time he came back, she was there to greet him. He wanted to tell her she couldn't have it both ways, but he was just as guilty.
Homeostasis was the name of the game and Dr. Sheldon Lee Cooper was no loser.