#4.22

Sam starts blaming Dean for what he's going to do (work with Ruby) way back in 3.09 because Dean isn't going to be around to be Sam's mommy, which is going to force Sam's hand.

After Dean comes back, Sam actually blames Dean for him working with Ruby by saying Dean wasn't there to protect him (4.04).

Dean repeatedly begs Sam not to work with Ruby and is ignored repeatedly (3.03, 3.04, 3.09, 3.16, 4.01-4.04, 4.12-4.22).

After telling Dean to open up to him and trust him (4.08), Sam calls Dean weak and pathetic for being traumatized by hell and says Dean is holding him back and therefore deserves to be lied to because he can't be of use (4.14) Sam says it's not what he really thinks when they both know it is (and Sam repeats it to other characters in 4.16, and 4.18) and then he admits it's the truth again to Dean's face in 4.21.

Sam accuses Dean of not trusting him enough (4.21).

Bobby blows up at Dean for not supporting Sam enough and calls him a pansy after Sam strangled Dean near unconscious, and tells him family is supposed to make you miserable (4.22).

Dean tries to reach out to Sam and Zachariah and Cas actively prevent him from doing so (Cas only at first) (4.22)

Zachariah (5.01) and Cas (5.02) both tell Dean the apocalypse is his fault because Dean didn't reach Sam in time to stop him from killing Lilith.

Dean says Sam hurt him, Sam is the one Dean depended on the most and Sam hurt him in ways he can't even voice (5.01). Sam apologizes, but then in the very next episode, shoves Dean into a wall for not trusting him like Dean is crazy and irrational when Sam doesn't even trust himself (5.02).

Sam says he thinks they should go their separate ways and is shocked when Dean agrees easily. Dean says that he spends more time worrying about Sam than he does doing the job right and time apart would be good. Sam reiterates that he's sorry and Dean gently says he knows Sam is (5.02).

Cas asks Dean if he's okay even without his brother, and Dean says "Especially without my brother. I mean, I spent so much time worrying about the son of a bitch. I mean, I’ve had more fun with you in the past twenty-four hours than I’ve had with Sam in years, and you’re not that much fun. It’s funny, you know, I’ve been so chained to my family, but now that I’m alone, hell, I’m happy." (5.03)

Sam says he wants back in. Dean objects, on the basis that he thinks they're stronger apart. Dean says they're each other's weaknesses and it's being used against them (5.04, but the weakness line is repeated from 3.03 and 3.16).

Zachariah pushes Dean into a future 2014 where Dean never met up with Sam again, and as a result, Sam said "Yes" to Lucifer, and billions of people died. All because Dean didn't want to be around Sam after being hurt and never reconnected with him (5.04).

Dean reconnects with Sam (5.04) even though he clearly doesn't want to, because the first case we see them on again, Dean struggles to trust Sam and leaves to go drink alone because he doesn't want to be around Sam (5.05).

Sam says part of the reason he went off with Ruby was to get away from Dean, because Dean is smothering. Dean is the problem in the relationship, because Sam feels inferior compared to him. Dean apologizes for being too smothering (5.05).