I definitely felt that Wilson was different right off the bat in Season 3, as I mentioned to srsly_yes above. With the combination of his divorce (especially finding out it was his wife cheating this time), the situation with Grace, then House getting shot, I guess it makes sense that he would change. Then the rift with House during the Tritter arc, and we get Wilson on antidepressants (I guess he just started using them around the time of 'Resignation' since House just started noticing the yawning side effect at that point).

I agree with you that Wilson's heart was always in the right place with House, even when his actions weren't wise.