Major depression is one of the most common mental diseases, and quite a number of patients are resistant to several psychopharmacological interventions, even when applying current treatment guidelines. To date, it remains unclear as to how the serotonergic system is implicated in treatment-resistance found in melancholically depressed patients.

In this study, we examined the involvement of post-synaptic 5-HT_2A receptors in the pathophysiology of treatment resistance in major depression with ¹²³I-5-I-R91150 SPECT, focusing on the frontal cortex and hippocampus.

15 unipolar antidepressant naïve (ADN) patients and 15 treatment-resistant depressed (TRD) patients, all of the melancholic subtype, matched for age and gender were studied. All subjects were antidepressant free when they underwent a static ¹²³I-5-I-R91150 SPECT scan.

Compared to ADN patients, TRD patients displayed significantly less 5-HT_2A receptor binding index (BI) in the dorsal regions of the prefrontal cortex and in the anterior cingulate cortex. No hippocampal 5-HT_2A receptor BI differences were observed.

Our results suggest that when confronted with treatment resistance in melancholic depression the 5-HT_2A receptors in the DPFC-ACC axis are significantly more down-regulated when compared to depressed ADN patients. This might to some extent explain the observed continued cognitive problems and might reflect the long-term serotonin depletion with reduced neurogenesis in treatment resistant patients.