Major depression is one of the most devastating disorders as measured by years of lives lost and diminished quality of live. According to treatment guidelines, mild depression should mainly be treated by psychotherapy, but moderate and severe disorders need very often pharmacological treatment. Drug therapy has several limitations: delay in treatment response, lack of efficacy, pharmacokinetic interactions, unwanted effects and unsatisfactory compliancy, especially in the long term treatment. About 30%-40% of moderate to severely depressed patients do not achieve remission after 2 antidepressant trials. They subsequently undergo treatment trials which are mainly based on the clinical practice of their prescriber. This is frequently a scientifically uninformed ‘‘trial and error'' approach. Indeed, solid evidence concerning individual therapeutic approaches is lacking. Electroconvulsive therapy is widely considered as an efficient treatment of last resort. But it is associated with cognitive side effects and high relapse rates. Its use is limited by availability and sometimes a negative perception by the public. Therefore, there is a need to develop alternative treatment approaches. Despite tremendous advances in genetics, neuroimagery, basic neurosciences and other research areas, depression is still considered as a “heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism” (2). In this thesis, we discuss the concept, the clinical course and unmet needs in the treatment of major depression based on selective reviews. A particularly troublesome aspect, emergent suicidality during antidepressant treatment, is illustrated by own work. Electroconvulsive therapy as the paradigmatic, controversial somatic treatment of depression is described, besides newer techniques such as repetitive transcranial magnetic stimulation. We present also our own contributions in the field of neurostimulation, especially magnetic seizure therapy, vagus nerve stimulation and deep brain stimulation and discuss their place in the treatment armamentarium of depression. We outline ongoing research activity to treat severe depression by modulation of glutamatergic neurotransmission using ketamine in a translational approach. We hope to contribute through our studies to better treat and understand depression, one of the major challenges in the field of mental disorders.