Lyric discussion by KGYIH 

Cover art for O' Sister lyrics by City and Colour

I think this song is about depression. Lines like "But the blackness in your heart it won't last forever" or "That's causing you such pain. Does it have something to do with the pills they gave to you?" are actually talking about a person who is lost and sad, and they gave him/her pills to recover. My psychologist diagnosed me with depression, and I feel identified with this song. I mean... "O' Sister, what's wrong with your mind?" This song is clearly about depression.

My Interpretation