Becomes Harsher in Hindsight when Rarity finds herself in the pre-Grimdark world, where everything's back to normal, and realizes she doesn't want it. But in order to get that world back, she realizes she'll have to murder Opal again. She really doesn't hesitate.
Heck, several posts across the blog imply that the Doctor (similar to Pinkamena above) knows what he's become, hates himself for it, but doesn't know how he can ever go back. And despite his protests, he does seem to suffer from incredible loneliness without Derpy by his side.
This post which is what happens when he's given crayons, starts out funny...then deteriorates to this. Of course, one could argue that it's all played for (dark)laughs.
The ongoing drama between the newPinkamena and her..."boyfriend", The Master. Being as obsessed with him as she is, hearing that he might have been cheating on her had quite an effect. So far, it seems that it'll take quite some time for either of them to totally recover.
In Ask Bubblini DaVinci Berry, when someone calls Bubble Berry out, for killing people, his reaction is this to many. It shows that even he is sick and tired of being seen as just a murderer and nothing more. And even says that he'd rather kill himself...
While its still awesome, having Dinky beating the crap out of the Discorded Doctor while Derpy watches on in terror with a crying Sparkler is utterly heartbreaking.
Trixie's horriblefate in Ask Genie Twilight. Doubles as horrific. Although it later turns out to be a simulation, in addition to being a fan submitted comic that is noncanon.
The "Reunion" arc of Ask Twixie Genies. Twilight, after spending the last half a year believing she would never see her friends again, finally reunites with them...only for Applejack and Rainbow Dash to do a complete 180 and turn on her, accusing her of abandoning them when none of what happened was her fault. Twilight outright tells them, tearfully, that she was scared to death of never seeing them again, that there was no way for her to get back to them on her own, and that all she ever wanted since becoming a genie was to be with her friends again. And yet, despite all this, AJ and RD still insist on being petty, hateful bitches, all because Twilight dared to not write to them when she was trapped against her will in her bottle/cave.
Rainbow Dash has a My God, What Have I Done? reaction upon being told that Twilight couldn't write them at first...but Applejack is still furious. Why? Because she'd been worried and missing Twilight, only to find out Twilight had been ABLE to contact them but chose not to for so long, causing her worry to turn into betrayed rage. Seeing Applejack, who is normally strong willed, break down crying recounting this is rather crushing.