I've never tried it but there is an app for Qmail (server side) that when an email is received at the server, the mail program sends a msg back to the sender asking for confirmation. Once confirmation is received back from the server (as a response to the email), Qmail will add that sended to an 'ok' list, thus allowing all following email thru from that addr. Emails that don't get confirmed go into a 'deny' folder, not allowing them thru going forward.
ie...Spam senders are porked cuz they usually don't respond to emails and thus get blocked...
the bad part is that legitimate folks will be like WTF...but once you work thru the initial confirmation, it would prolly work great..
again, this is on the server-side, so you would need a mail provider that offers this.
...can't remember the name of the Qmail mod