Migraine and mood depression demonstrate a high clinical relation and share, also with pain, neurobiological mechanisms, particularly neuro-transmettitorial and phlogistic ones. The choice of an antidepressant to treat both depression and migraine is determined by its efficacy, safety, and tolerability. Antidepressants share comparable effectiveness for the treatment of depressive disorders, but their efficacy on headache varies widely: Tricyclic antidepressants are more effective than SNRIs and SSRIs, but demonstrate dose-limiting side effects.