While antidepressant medications and psychotherapy are often effective in the treatment of major depressive disorder, approximately one-third of patients do not respond adequately to these treatments. Treatment-resistant depression (TRD) is associated with a higher rate of suicide attempts, a higher number of hospitalizations, and more frequent comorbidity with other diseases, resulting in higher treatment costs than those without TRD. For these reasons, the search for alternative treatments for TRD is still ongoing, and interest in biological treatments has been increasing in recent years. In this section, the journey of biological treatments used in the treatment of depression from past to present, their mechanism of action, and application methods have been compiled in light of current information.