Patients for whom the diagnosis of depression was established, yet did not respond to adequate treatment are defined as suffering from resistant depression (RD). As 20-30% of depression is resistant, depression subtypes with distinct pathophysiology are considered.

The neurobiological approach to RD aims to identify and characterize these subtypes. Different underlying mechanisms which may play a role in RD include: tolerance (“escape”), a “kindling” type of phenomenon, or no response to begin with. There are several types of underlying pathophysiological mechanisms proposed for RD, including: HPA axis hyperactivity, thyroid abnormality, estrogen in postmenopausal women, lower availability of l-tryptophan to the brain, frontal or parietal perfusion defects, genetic factors, thyroidal abnormalities, a combination of 5HT/HPA axis and brain lesion, 5HT, NA and HPA abnormalities, sleep abnormalities and immunological factors.

In order to gain better knowledge of these mechanisms, studies of RD patients providing a careful evaluation of the HPA axis and of serotonergic and noradrenergic responsivity, as well as evaluation of the thyroid system, are warranted. Tryptophan depletion and NE depletion have proven to be effective tools in the study of depression and might be of particular interest in RD. Brain imaging, pre- and post-treatment, and a dichotomous comparison of changes in brain activity in patients who responded to treatment for RD might be of value. However, these have not yet been studied systematically.

Patients with RD suffer greatly and need to be treated. Various underlying psychobiological abnormalities might assist us in tailoring treatment especially to the patient.