Patients belonging to Group 1 (Major Depression) and 2 (Bipolar Disorder) will be tested with psychometric and functional scales at baseline (T0) and after 4 weeks of pharmacological therapy (T1), to evaluate clinical and functional response to treatment. MDD patients will be screened for the lifetime and recent occurrence of clinically meaningful suicidal ideation and behavior prior to recruitment (-T1). Moreover, in the MDD group, the emergence of clinically meaningful suicidal ideation and behavior will be evaluated at the baseline (T0) and after 4 weeks (T1) by means of the C-SSRS, accordingly to the routine clinical practice. Furtherly, to accomplish the pursues of this research, the two groups will undergo neuroimaging evaluation and a blood collection at the two timepoints for measuring the expression of ncRNA before and after treatment. Meanwhile, a lumbar puncture (LP) for CSF collection will be carried out at the baseline, measuring central levels of Negr-1 and other biomarkers of neurotropism potentially related to the aforementioned role of Negr1 in MDD. Group 3 will be comprehensive of 10 subjects without current or previous diagnosis of psychiatric disorders (healthy controls), who will be evaluated at baseline with psychometric and functional scales, neuroimaging and blood samples collection for ncRNA. Data obtained by the multimodal assessment of HCs at the baseline will be employed as normalization features in the statistical analysis of patients' data.

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).

Inclusion Criteria:

• GRUPPO 1: Recently diagnosed MDD, ongoing depressive episode, as determined by SCID-CV;
• Clinical indication to switch from current antidepressant therapy to venlafaxine due to lack of efficacy and/or tolerance and/or compliance.

GRUPPO 2: Recent diagnosis of BD with a current depressive episode, as determined by SCID-CV;

- absence of antidepressants in the patient's drug regimen.

GRUPPO 3: No diagnosis of psychiatric disorders made as a result of SCID-CV.

Exclusion Criteria:

• GRUPPO 1: - treatment with venlafaxine ongoing or within 6 months before the recruitment
• concomitant treatment with an irreversible MonoAmine Oxidase Inhibitor (I-MAO) or interruption of the IMAO treatment before 14 days from the recruitment;
• pregnant and breastfeeding woman;
• Lifetime comorbidity for psychotic disorders, as determined by the SCID-CV;
• Lifetime or recent history of suicide attempts or suicide-related behaviors and ideation (lifetime and/or recent C-SSRS Ideation or Behavior sub-score >0);
• Current, clinically meaningful, substance use disorders;
• Current comorbidity with neurological conditions or severe head trauma; -Neuropsychological diagnosis of intellectual disability;
• Presence of contraindications to lumbar puncture or MRI
• known hypersensitivity to the active substance venlafaxine or to any of the excipients
• Women of Childbearing Potential without a negative pregnancy test and not undertaking a high effective anticonception treatment at the recruitment

GRUPPO 2:

• Lifetime comorbidity for psychotic disorders, as determined by the SCID-CV;
• Current, clinically meaningful, substance use disorders;
• Current comorbidity with neurological conditions or severe head trauma;
• Neuropsychological diagnosis of intellectual disability;
• Presence of contraindications to lumbar puncture or MRI.

GRUPPO 3:

• Current or previous lifetime therapy with antidepressants
• Current, clinically meaningful, substance use disorders;
• Current comorbidity with neurological conditions or severe head trauma;
• Neuropsychological diagnosis of intellectual disability;
• Presence of contraindications to MRI scan