For decades, the most severe, protracted and therapy-resistant forms of major 
depression have compelled clinicians and researchers to look for last resort 
treatment. Early psychosurgical procedures were hazardous and often associated 
with severe and persistent side effects including avolition, apathy and change 
of personality. With the introduction of psychopharmacological treatments in the 
1950s, the frequency of ablative procedures declined rapidly. The past decade, 
however, has witnessed the resurgence of surgical strategies as a result of 
refined techniques and advances such as high frequency stimulation of deep brain 
nuclei. Recent data suggest that the overall effect of high frequency 
stimulation lies in the functional inhibition of neural activity in the region 
stimulated. Contrary to other psychosurgical procedures, high frequency 
stimulation reversibly modulates targeted brain areas and allows a postsurgical 
adaption of the stimulation parameters according to clinical outcome. With 
increased understanding of the brain regions and functional circuits involved in 
the pathogenesis of psychiatric disorders, major depression has emerged as a 
target for new psychosurgical approaches to selectively and precisely modulate 
neural areas involved in the disease process. Recent studies of minimally 
intervening procedures report good clinical outcome in the treatment of 
therapy-resistant forms of major depression. High frequency stimulation was 
successfully applied in several small samples of patients with 
treatment-resistant depression when the stimulation focused on different areas, 
e.g., nucleus accumbens, the lateral habenula or cortical areas. Nevertheless, 
the reticence toward psychosurgery, even for those patients suffering from the 
most debilitating forms of depression, still prevails, even though recent 
studies have shown significant improvement in terms of quality of life with the 
limitation that the number of treated cases has been small. In any event, valid 
and unambiguous criteria for patient eligibility have yet to be refined and 
standardized. In this review, we suggest possible standard criteria for the 
application of deep brain stimulation on patients suffering from otherwise 
treatment-resistant depression.