Objectives: To identify in patients with major depression different peripheral markers of neuroinflammation in relation to affective symptoms (anxiety, depression, irritability), fatigue and cognitive symptoms; and its relationship with the response to antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs).
Methodology: This is a prospective observational cohort study in patients with major depression naturally subjected to treatment with SSRIs. For this, 30 patients with major depression attended in the Outpatient Psychiatry Consultations will be selected. All of them will be evaluated at baseline and after 3 months of treatment, collecting demographic and clinical variables, Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) psychiatric diagnoses, psychopathological scales and immunological and biochemical variables. The correlation between immunological markers and affective and cognitive symptoms at baseline, as well as their variation with treatment, will be analyzed. A group of 20 healthy subjects will be used as a control group.
Subsequently, a bivariate comparative analysis will be carried out, where the statistically significant or marginally significant variables associated with psychopathological variables will be used to build a multivariate binary logistic regression model.
Age between 18 and 65 years
Clinical diagnosis of major depression according to DSM-5 criteria made by a psychiatrist applying the Structured Clinical Interview for DSM-5 (SCID-5).
Eligible for receiving antidepressant treatment for major depression.
Who have received antidepressant, antipsychotic or euthymizer treatments in the 6 weeks prior to inclusion in the study.
Who present concurrent psychotic symptoms.
Who present disorders due to alcohol or drug use, with active consumption during the last 3 months.
Pregnant women.
The subjects that will participate in this study will be outpatients attended in the Outpatient Psychiatry Consultations of the Hospital Universitari Germans Trias i Pujol (Badalona, Spain) clinically diagnosed with major depression and eligible to receive antidepressant treatment with SSRIs. The control group will be made up of healthy subjects, using the same inclusion and exclusion criteria except for the psychiatric diagnosis.
Cohort
Prospective
SSRI
DrugOutpatients with a diagnosis of major depression in the Psychiatry Outpatient Clinics will be evaluated for recruitment. * Recruitment visit: It will be carried out by one of the psychiatrists participating in the study. The patient will be informed about the study and written consent will be requested. Subsequently, the inclusion and exclusion criteria will be reviewed, and all demographic and clinical variables will be collected. * Baseline visit: One of the psychiatrists will interview the patient and apply the semi-structured clinical interview and the psychopathological evaluation questionnaires. In addition, a blood draw will be performed for serum collection, spectral cytometric analysis of lymphocyte subpopulations and obtaining peripheral blood mononuclear cells (PBMCs). * Follow-up visit after 3 months of treatment: Clinical variables will be collected and the same procedures will be performed as during the baseline visit. Not in the control group.
Treatment Response
The response to treatment will be assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) scale scores. The MADRS scoring instructions indicate that a total score ranging from 0 to 6 indicates that the patient is in the normal range (no depression), a score ranging from 7 to 19 indicates "mild depression", 20 to 34 indicates "moderate depression", a score of 35 and greater indicates "severe depression", and a total score of 60 or greater indicates "very severe depression".
Lymphocyte subpopulations
For the study of lymphocyte subpopulations, a multidimensional flow cytometry panel has been designed. The panel includes markers for the identification of the most representative subpopulations of T cells (Th1, Th2, Th17, Th1/17, Treg, naïve cells, central memory and effector memory, total Tfh, Tγδ1, Tγδ2, Tγδ17, Tγδ1/17...) and monocytes as well as activation markers (HLADR, CD38), inhibitory checkpoints (PD1, TIM3) and markers of tissue migration and response to chemokines (CCR2, CX3CR1, CXCR6). The results of expression markers and subpopulations will be expressed as percentage over total lymphocyte counts.
Biochemical variables
From the serum samples, the analysis of C-reactive protein and immunoglobulins will be performed by Chemiluminescence immunoassay and expressed in mg/dl. The study of pro-inflammatory and anti-inflammatory cytokines (IL-1, IL-6, Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-12, IL-23, IL-17, IL-22, TGFbeta, IL-10, IL-4) and neurogenesis/neuroinflammation factors (BDNF, VILIP-1, β-Nerve Growth Factor (NGF), sRAGE, chemokine C-X3-C motif ligand 1 (CX3CL1), Soluble triggering receptor expressed on myeloid cell-2 (sTREM-2)) in serum using Multiplex Bead-based Immunoassay technology and expressed in pg/ml. The study of the relative expression of miRNAs (miR-155, miR-126, miR-223, miR-146a, miR-21, miR-124) will also be carried out from serum samples using real time quantitative PCR (RT-qPCR).
Single-cell CITEseq
Frozen samples will be used to perform lymphocyte transcriptomic and proteomic study at the single cell level, allowing the study of the immune system in great depth. For this, Single cell RNA sequencing technology (CITEseq) will be used. CITEseq is a multimodal single-cell phenotyping method that uses antibody-bound oligonucleotides that act as synthetic transcripts that are captured during single-cell RNA-seq library preparation protocols. This allows immunophenotyping of cells with a potentially unlimited number of markers and analysis of the transcriptome using single-cell sequencing approaches such as those developed by 10x Genomics.
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