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

ObjectivesQuite 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.MethodsWe examined the involvement of post-synaptic 5-HT2A receptors in the pathophysiology of treatment-resistance in unipolar melancholic major depression with 123I-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.ResultsCompared to ADN patients and healthy controls, TRD patients displayed significantly lower 5-HT2A receptor binding index (BI) in the dorsal regions of the prefrontal and the anterior cingulate cortex. No significant 5-HT2A receptor BI differences between ADN patients and controls were observed.ConclusionsAt the cortical level, 5-HT2A 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-HT2A 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'.

► Frontal cortical 5-HT2A receptors are down-regulated in treatment-resistant depression (TRD). ► In TRD this down-regulation is most significant in dorsolateral-cingulate cortical areas. ► Compared to controls 5-HT2A receptors do not differ in first-episode depression.