Precision Psychiatry for Depression: Immune Response and Affective Symptoms as Predictors of Response to Antidepressants

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