I can think of one instance where it was the chick I was crushing on hard.
I did something that I usually wouldn't do that day, I actually broke out of my fucking shell and attempted to initiate a conversation with "Hi".
Know what I got in return? Nothing. Maybe she didn't hear me, maybe she chose to selectively ignore me, I don't know. It didn't matter. The point is that I put myself out there, I raised myself 50,000 feet into the air for the first time in my life, and fate chose to smack my heart at it's most vulnerable, sending me back to a chasm of depression and anxiety.
*and just saying, but I know I'm not entitled to a reply, and it really may have been that she didn't hear me. But to me, it was a significant failure that would go on to permanently set me back in terms of depression.