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 treatmentresistance.Currently, the underlying neurobiological mechanism as to how repetitive transcranial magnetic stimulation (rTMS) can alter depressive states also remains unclear.Animal data suggest that its influence could occur at the neurotransmitter level, such as modulation of the serotonin system.We conducted two studies.Firstly, we examined the involvement ofpost-synaptic 5-HT2A receptors in the pathophysiology of treatment resistance in unipolar melancholic major depression with 123I-5-I-R91150 SPECT.15 antidepressantnaive (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.Secondly, we examined the neurobiological impact of 10 high-frequent (HF)-rTMS sessions applied to the left dorsolateral prefrontal cortex (DLPFC) on postsynaptic 5-HT2A receptor binding measured with 123I-5-I-R91150 SPECT only in TRD patients.Compared to ADN patients and healthy controls, TRD patients displayed significantly lower 5-HT2A receptor binding index (BI) in the dorsal regions of the prefrontal cortex.Successful HF-rTMS treatment correlated positively with 5-HT2A receptor BI in the DLPFC bilaterally and correlated negatively with right hippocampal 5-HT2A receptor uptake values.Our results suggest that when encountered with treatment resistance, the 5-HT2A receptors in the prefrontal cortex are significantly down-regulated.Our treatment results indicate that HF-rTMS affects the serotonergic system.Our data also suggest that this kind of treatment affects 5-HT2A receptor BI in the DLPFC and in the hippocampus in different ways.However, whether this assumed underlying pathophysiological mechanism is due solely to abnormalities in the serotonergic system remains to be answered.