Refractory Depression, for Schatzberg and contributors (1983) is the non-response to a proved antidepressants adequate in doses, in time and plasma concentration; although it has been defined by multiple clinicians authors, among them: Freyhan (1974), Feighner (1980), Akiskal (1983), Fawcett and Kravitz (1985), Feinberg and Halbreich (1986), Paykel (1989) and Nierenberg and Amsterdam (1990). The refractoriness may change according to clinic dimension, socio-cultural, temporal, chronological and pathogenic. The basic alternative for every antidepressant treatment is the use of ISRS or tricyclics, as first line drugs. The first alternative, is adding a tricyclic to the ISRS or viceversa; the second alternative, consists in adding lithium to first line antidepressants, which exhausted revision is done by Johnson (1991); the third alternative, is the use of IMAO, but the only one that has demonstrated to be effective enough in refractory depression, is the tranilcilpromine according to Nolen (1994) revision, who says that in a near future the IMAO Type A could be considered first election drugs together with the ISRS and tricycli. Within the second order alternatives, we found: the role of thyroid hormone, revised by Gorman and Hatterer (1994), give us evidence that it is each time bigger in the last years, than with lithium addness, the adding T3 to antidepressants has eclipsed. The combination with antidepressants of serotonergic action, as it is the fluoxetine association, buspirone and trazadone. seems to be an effective association in refractory depressions, according to Lader (1991) and Bakish (1994). The role of psychostimulants (Ps), which are indicated in refractory depressions, only in patiens that for some reason do not tolerate the ISRS and tryciclics. The rate of estrogens, although is not conclusive, because of the low profile of collateral effects, can let us have it as secondary alternative for the refractory depression in women. The treatment of refractory depression involves several degrees of disorder, among them we find serotonergic activity and central adrenergic, the hyperactivity of the HPA axis, the structural defects and brain metabolics.