Is treatment-resistance in unipolar melancholic depression characterized by decreased serotonin₂A receptors in the dorsal prefrontal - anterior cingulate cortex?

Objectives: Quite a number of patients diagnosed with major depression are resistant to several well carried-out psychopharmacological interventions. It remains unclear as to how the serotonergic system is implicated in the phenomenon of treatment-resistance.

Methods: We examined the involvement of post-synaptic 5-HT(2A) receptors in the pathophysiology of treatment-resistance in unipolar melancholic major depression with (123)I-5-I-R91150 SPECT. 15 antidepressant-naïve (ADN) first-episode depressed patients, 15 antidepressant-free treatment-resistant depressed (TRD) patients and 15 never-depressed individuals, matched for age and gender were studied.

Results: Compared to ADN patients and healthy controls, TRD patients displayed significantly lower 5-HT(2A) receptor binding index (BI) in the dorsal regions of the prefrontal and the anterior cingulate cortex. No significant 5-HT(2A) receptor BI differences between ADN patients and controls were observed.

Conclusions: At the cortical level, 5-HT(2A) receptor BI does not significantly differ in first-episode melancholic depressed patients compared to healthy controls. This observation might imply a limited short-term impact on the serotonergic system in first episode depression. Our results also suggest that when encountered with treatment-resistance, the 5-HT(2A) receptors in the DPFC-ACC axis are significantly down-regulated. However, whether this assumed underlying pathophysiological mechanism is due solely to abnormalities in the serotonergic system remains to be answered. This article is part of a Special Issue entitled 'Anxiety and Depression'.