The present study investigated whether it is possible to predict the medium term response to venlafaxine using biological markers and psychophysiological methods.Fourteen (14) patients aged 21–60 years suffering from Major Depression according to DSM-IV were included in the study.The SCAN v 2.0 and the IPDE were used to assist clinical diagnosis. Patients were investigated with electrooculogram (EOG), Pattern-Reversal Visual Evoked Potentials (PR-VEPs), Dexamethasone Suppression Test (DST), d-fenfluramine Challenge Test, and brain Single Photon Emission Tomography (SPECT). Venlafaxine 150–225 mg per os daily was administered. The follow-up period was 2 years.Chi-square test and ANOVA were used for the analysis of data.There was a lower left globus pallidus regional cerebral blood flow in patients with better response. On the contrary, chronic patients were closer to normality.The results of the current study provide preliminary evidence concerning our ability to predict response to venlafaxine and to understand its way of action.