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.

Depression is the mental disorder that has the highest prevalence, affecting approximately 16% of the general population and having a great impact on the global functionality of patients. According to the World Health Organization (WHO), depression will be considered the main cause of disability in 2030. At the end of the last century, a large part of the studies on the neurobiological bases of depression evolved from the monoaminergic hypothesis. This theory proposes that the etiopathogenesis of depression would be directly related to a reduction in monoaminergic activity (noradrenergic, serotonergic or both) in the central nervous system (CNS). From there, it was postulated that the antidepressant action of various drugs could be due to an enhancement of neurotransmission as a consequence of the increase in the concentration of monoamines at the level of the synaptic space. This monoaminergic hypothesis, however, does not answer some important questions such as what causes these monoaminergic alterations? Or how do we explain the existence of 30% of patients refractory to antidepressant treatment? For this reason, there has been growing interest in recent years in other theories that focus on the immune and endocrine systems.

The immune system and the nervous system share the functions of recognizing objects, discerning their qualities and generating an adaptive response related to them. The inflammatory reflex (innate immunity) depends on the detection of specific molecular patterns in invaders, but not expressed by own tissues. One of the first observations on the relationship of the innate immune system to the CNS was the increase in blood concentrations of inflammatory biological markers, such as C-reactive protein (CRP) and fibrinogen, in patients with depression. Since then, and especially in the field of major depression, there is a growing body of literature supporting its link with inflammation: frequent comorbidity with inflammatory diseases such as coronary heart disease or rheumatoid arthritis; presence of elevated levels of proinflammatory cytokines; potential of exogenous proinflammatory cytokines to induce depressive symptoms; the association of levels of peripheral markers of inflammation with the severity of depression; potential of antidepressants to inhibit inflammation; antidepressant effects of anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), etc. In addition to proinflammatory molecules, alterations in the levels of lymphocyte subpopulations such as T helper type 17 (Th17) or T regulatory cells (Treg) have recently been characterized in patients with major depression that could be related to the neuroinflammatory process.

The impact of inflammation on behavior, however, is not only associated with depression itself, but with specific dimensions of symptoms such as alterations in motivation and motor activity (fatigue, psychomotor impairment) and with greater sensitivity to the threat (anxiety, arousal, alarm).

The results of this project will contribute, first of all, to a better understanding of the immunological aspects of depressive processes, which will favor the possibility of developing new targets for future treatments of this disease. Secondly, the results will help identify biological and clinical markers that predict response to antidepressant treatment.

Hypothesis

1. The combination of immune response biomarkers (acute phase inflammation, cytokines, hypothalamic-pituitary-adrenal (HPA) axis, oxidative and nitrosative stress, activation of microglia and Th17 and Tγδ17 lymphocytes, Treg and neurogenesis), symptoms of positive and negative valence systems of Research Domain Criteria (RDoC) (depression, anhedonia, fatigue, anxiety) and cognitive dysfunction allows to establish a prediction about the response to treatment with SSRI antidepressants in patients with major depression.
2. Symptoms included in RDoC positive and negative valence systems (depression, anhedonia, fatigue, anxiety), as well as cognitive dysfunction, are positively related to biomarkers of acute phase inflammation, proinflammatory cytokines, HPA axis, oxidative and nitrosative stress, activation of microglia and Th17 and Tγδ17 lymphocytes and negatively related to biomarkers of anti-inflammatory cytokines, Treg and neurogenesis in patients with major depression compared to healthy controls.
3. The improvement of symptoms included in the positive and negative valence systems of RDoC (depression, anhedonia, fatigue, anxiety) as well as cognitive dysfunction after antidepressant treatment with SSRIs are related to the reduction of biomarkers of acute phase inflammation, proinflammatory cytokines, HPA axis, oxidative and nitrosative stress, activation of microglia and Th17 and Tγδ17 lymphocytes, and increased anti-inflammatory cytokines, Treg and neurogenesis.

Primary Objective

1. To assess the combination of immune response biomarkers (acute phase inflammation, cytokines, HPA axis, oxidative and nitrosative stress, activation of microglia and Th17 and Tγδ17 lymphocytes, Treg and neurogenesis), symptoms of positive and negative valence systems of RDoC (depression, anhedonia, fatigue, anxiety) and cognitive dysfunction as predictors of response to SSRI antidepressant treatment in patients with major depression.

   Secondary Objectives

2. To evaluate the relationship between biomarkers of immune response (acute phase inflammation, cytokines, HPA axis, oxidative and nitrosative stress, activation of microglia and Th17 and Tγδ17 lymphocytes, Treg and neurogenesis) and symptoms of the positive and negative valence systems of RDoC (depression, anhedonia, fatigue, anxiety) and cognitive dysfunction in patients with major depression compared to healthy controls.

3. To evaluate the relationship between biomarkers of immune response (acute phase inflammation, cytokines, HPA axis, oxidative and nitrosative stress, activation of microglia and Th17 and Tγδ17 lymphocytes, Treg and neurogenesis) and symptoms of the positive and negative valence systems of RDoC (depression, anhedonia, fatigue, anxiety) and cognitive dysfunction in patients with major depression in relation to response to treatment.

4. To define the phenotype and transcriptome of the lymphocyte subpopulations of patients with major depression before and after treatment.

5. To evaluate the kinetics of the lymphocyte subpopulations of patients with major depression at different times of treatment.

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.
• Who have serious or unstable medical disorders, Addison's or Cushing's disease, systemic inflammatory or autoimmune diseases, or primary or secondary immunodeficiencies.

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.