In this clinical trial, the investigators will recruit a cohort consisting of 10 patients with MDD who will be evaluated at baseline (T0) and at 4 weeks from the setting of drug treatment with venlafaxine (T1). The sample consists of patients already being treated with antidepressant drugs (e.g., drugs SSRI/SNRIs) for whom it was necessary to switch to venlafaxine therapy medication due to poor/no response or poor tolerability to current therapy according to the indications of the major clinical guidelines for the treatment of MDD and completely independently of study participation.

To distinguish clinical variations related to the clinical course of depression, the investigators will also recruit a cohort of 10 patients with bipolar disorder, suffering from a current depressive episode (Group 2) and who will be assessed both at T0 and after 4 weeks (T1). To identify markers blood and neuroimaging markers of MDD, will be recruited 10 healthy controls without current psychiatric history (Group 3), who will be evaluated only at baseline (T0). After signing informed consent and recruitment, demographic data (age, sex, level of education, etc.) and clinical data (past and current diagnoses, comorbidities, habits smoking, past therapy, age at onset, etc.) were collected from patients and healthy controls, as possible variables confounders to the clinical course of MDD. Patients with MDD and bipolar disorder will be tested with psychometric and functional scales (BPRS, MADRS, HDRS, GAF) at baseline (T0) and after 4 weeks of therapy (T1), to assess the change in clinical picture.

The presence or occurrence of suicidal ideation or behavior in patients with MDD will be assessed by clinical interview and administration of the C-SSRS at baseline (T0) and after 4 weeks of therapy (T1). (In addition, the three groups at baseline will perform structural and functional brain MRI associated with EEG and the collection of two peripheral venous blood samples. All assessments will be repeated at T1 (at 4 weeks) for Groups 1 and 2 of MDD and DB patients. More over, at baseline, patients in Group 1 and 2 will undergo spinal tap (PL), with collection of a sample of fluid cerebrospinal fluid, for measurement of central levels of Negr-1 and other biomarkers of neurotropism potentially involved in Negr1 activity in MDD. In the cerebrospinal fluid and peripheral blood biological samples, obtained from the three groups of subjects, the levels of gene expression (mRNA) and protein levels of Negr-1 and other biomarkers involved in the modulation of the antidepressant response operated by Negr-1, will be assessed by digital droplets PCR (ddPCR) and enzyme-linked immunosorbent assay (ELISA). The expression levels of the following genes involved in the NEGR-1 pathway will be tested in cerebrospinal fluid (CSF) cells. The genes include Abeta 1-42, tau, P-tau, MAPT, MAP2, GAP43, NCAM, SYP, VEGF, IGF-1, BDNF and FGF-2. Their expression levels will be tested in the CSF by Droplet Digital PCR (QX200 ddPCR BioRad), using Taqman Probes. Several housekeeping genes will be used for normalization. Biological samples will be processed by the laboratory of neurodegenerative and demyelinating diseases of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. Neuroimaging scans will be collected from MDD patients, BD patients and healthy controls at T0, and for MDD and BD patients at T1. The scans of neuroimaging will be performed using a 3-Tesla Philips Achieva MRI scanner and with an MRI-compatible EEG system). The investigators will collect data resting-state, at baseline and after 4 weeks of follow-up. The administration of drug therapy with venlafaxine (IMP of study) in MDD patients will be done according to normal clinical practice, following the indications in the CPR, the package insert and following medical prescription based on the clinical evaluation. The intervention study is related to the extra standard of care MRI that the MDD and BD patients will perform at baseline and after 4 weeks and to the cerebrospinal fluid collection (an invasive procedure not included in clinical practice for the management of these patients).