I just recently tried to upgrade a Drupal 6.16 installation to the recommended 6.22. It fell in a crumpled heap! I did the upgrade using drush and it produced loads of warning messages about disabled modules because the 'module wasn't compatible with the new version' and also did some database changes which I'm pretty certain was what broke the system completely.
I have reverted to 6.16 and restored the database and all is well now, but I'm a bit unsure how to proceed as it feels as if I really should do the security upgrades.
I'm afraid I lost the output from drush where all the warning messages were shown because I just wanted to undo the mess.
I can possibly try again with (yet another) copy of the site and show the error messages here if that might help.