Major Depressive Disorder (MDD) is a common and debilitating neuropsychiatric disorder with high economic and societal impact. Approximately 30% of subjects with MDD achieve full remission after treatment with conventional antidepressants resulting in a relevant percentage of patients suffering from treatment resistant depression (TRD). Treating TRD is a difficult challenge for psychiatrists due to the complexity of this disabling condition. In fact, TRD is generally associated with a poorer outcome, higher suicidal risk, more severe psychosocial impairment and physical disability when compared to MDD. This book provides new research on treatment options, challenges and the future directions for individuals with TRD.