Depression is a disabling disorder associated with considerable comorbidity, risk of suicide and social consequences. Although antidepressants are among the most prescribed therapeutic agents, recent reviews highlight the significant percentage of depressed patients who fail to achieve a response or remission.

Although epidemiological and clinical data do not support severe depression as a separate illness category, and there is no consensus on the definition of "severe depression" regarding diagnostic scales, evidence suggest that the severity of depressive symptomatology may be associated with a worse prognosis and an increased mortality. Furthermore is there a perception that specific subpopulations of depressed patients e.g. melancholic patients or treatment resistant patients suffer of more severe forms of depression. The treatment of severely depressed patients is thus of major concern in view of the debilitating course of the disease.

Some early studies suggested that tricyclic antidepressants (TCAs) like clomipramine were more effective that selective serotonin reuptake inhibitors (SSRIs) paroxetine or citalopram in "endogenously" depressed patients. Other reviews report comparable efficacy of TCAs and SSRIs in patients with severe or melancholic depression, with SSRIs being better tolerated.

Recent data suggesting a surprisingly better differentiation of escitalopram, the active enantiomer of racemic citalopram, regarding effeicacy in more severely depressed patients (MADRS > 30 or > 35) versus SSRIs such as paroxetine and citalopram as well as versus the SNRI venlafaxine argue for a differentiated treatment approach, based on severity of symptoms.