The burden of depression as a severe illness with high suicidality and 
prevalence is immense. Despite substantial advancement in psychopharmacology and 
psychotherapy over the last decades a residual group of very ill patients with a 
chronic disease and high suicidal risk remains. Modern theories about the 
pathophysiology of depression are derived from studies examining the mechanism 
of antidepressants influencing the serotonergic (5-HT) and noradrenergic (NE) 
systems. Serotonergic fibers originate from the dorsal raphe nuclei (DRN), 
noradrenergic fibers from the locus coeruleus (LC). Both nuclei represent 
relatively small brain regions and both are controlled to some extent by the 
habenular complex. We propose the hypothesis of an overactivation of the 
habenula in human major depressive episodes (MDE's). Increased activation of the 
lateral habenular nucleus leads to the down regulation of the serotonergic, 
noradrenergic, dopaminergic systems and stimulation of the 
hypothalamic-pituitary-adrenal (HPA) axis. Functional inhibition of the lateral 
habenula via deep brain stimulation (DBS) has antidepressive properties. The 
hypothesis is based on the findings of a clinical imaging study examining the 
habenular after tryptophan depletion and on several animal studies which are 
discussed. Providing that our hypothesis will be validated by an analogous 
tyrosine depletion study and additional preclinical studies, the next logical 
step would be to directly test our hypothesis in patients. Possible criteria for 
patient selection, ethical issues and locus of DBS are carefully discussed.