The role of the neuroendocrine and immune systems in the pathogenesis of depression

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Review article

The role of the neuroendocrine and immune systems in the pathogenesis of depression Q1 Ewa

Ogłodek 1,*, Anna Szota 1, Marek Just 2, Danuta Mos´ 3, Aleksander Araszkiewicz 1

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Department of Psychiatry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun´, Poland Piekary Medical Centre, Department of General Surgery, Municipal Hospital in Piekary S´la˛skie, Poland 3 Health Care Centre Euro-Med Bytom, Poland 2

A R T I C L E I N F O

A B S T R A C T

Article history: Received 5 February 2014 Received in revised form 14 April 2014 Accepted 16 April 2014 Available online xxx

Objective: Development of depression is associated with the body’s response to prolonged stress, which adversely affects the functioning of the nervous, endocrine and immune systems. Prolonged stress can lead to the development of a so-called allostatic load and reduction of concentration of brain-derived neurotrophic factor. These changes result in impairment of neurogenesis and synaptic remodeling process. This article illustrates the involvement of key mediators of allostasis such as the neuroendocrine and immune systems, in the pathogenesis of depression. Method: The literature concerning the contribution of the neuroendocrine and immune systems to depression incidence was reviewed. Results: Development of depression is associated with disturbance of the body’s allostasis and inflammatory activation of the immune system. It leads to a chronic increase in the concentration of cortisol and proinflammatory cytokines, which results in an allostatic load. This load leads to neurodegeneration, eventually causing irreversible cognitive impairment and permanent disability. Conclusions: Determination of the concentration of chemokines and their receptors is an important indicator of activation of the immune and neuroendocrine systems. The activity of these systems reflects the severity of the disease and provides important information for effective antidepressant treatment. ß 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.

Keywords: Allostasis Depression Immune system Neuroendocrine system

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenetic hypotheses of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . Functioning of the neuroendocrine and immune systems in depression . Inflammatory activation of the immune system in depression . . . . . . . . The role of chemokines in the pathomechanism of depression . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

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Chronic stress induced by the rapid pace of life of many people in today’s world can lead to changes in nervous and immune

* Corresponding author. E-mail addresses: [email protected], fi[email protected] (E. Ogłodek).

system function and, consequently, the development of depression [1]. The development of depression is associated with a disruption of the internal homeostasis of the body by pathogenetic factors and with the activation of compensatory mechanisms leading to allostasis. Allostasis, in terms of neuropsychology, describes mental disorders on the basis of their pathogenesis, internal stability, immune and neuroendocrine factors and gene expression. Allostasis is the process of achieving stability of the internal

http://dx.doi.org/10.1016/j.pharep.2014.04.009 1734-1140/ß 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.

Please cite this article in press as: Ogłodek E, et al. The role of the neuroendocrine and immune systems in the pathogenesis of depression. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2014.04.009

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homeostasis disturbed by the action of pathogenetic factors. Achieving allostasis is possible due to cooperation of so-called mediators of allostasis, which includes the neuroendocrine system, the autonomic nervous system, the immune system and the substances secreted by it, such as the hormones of the hypothalamic-pituitary-adrenal (HPA) axis, catecholamines and cytokines [2–4]. Depression as a disease resulting from the accumulation of these processes indicates that allostasis gradually increases with the duration of the disease, the intensity of stressors and the number of depressive episodes. A report by the World Health Organization (WHO) stated that in 2030, depression may top the list of diseases with the highest risk factors of premature death and loss of the ability to work. Development of depression is associated with the disturbance of body allostasis. The annual incidence of the disease in the adult population is 6–12% [5]. Depression can co-exist with other somatic illnesses and may exist in a form of masked depression, which often remains unrecognized by physicians who are not psychiatrists. This means that approximately 10% of all adults (corresponding to a hundred million cases) within one year have symptoms of depression. Depression can have an episodic course, with complete remission or long periods without symptoms, and a recurrent course, with short periods of remission between episodes. It can also be a chronic disease, resistant to treatment. It is important to diagnose depression early, understand its basis, administer appropriate treatment and monitor the disease to prevent relapse after remission. Many theories are known to explain the basis of the pathogenesis of depression.

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Pathogenetic hypotheses of depression

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The oldest pathogenetic hypotheses are the monoaminergic hypothesis of depression, which indicates a deficiency of noradrenaline (catecholamine hypothesis) and serotonin (serotonin hypothesis) in the brain and the hypothesis associated with increased cholinergic transduction [6–8]. Monoaminergic ideas stimulated the development of research on depression, but simplified the complex mechanisms of pathogenesis of depression. Research in the psychopharmacology of depression, as well as noradrenergic and serotonergic neurotransmission in patients with depressive disorders, has shown that the two systems are coupled. The majority of people suffering from depression displayed a coexistence of noradrenaline (NA) and 5-hydroxytryptamine (5-HT) system dysfunction [6,7]. For many years, research on the pathogenesis of depression focused on the transformation and distribution of neurotransmitters (NA, 5-HT, dopamine-DA, acetylocholine-ACH) and their effect on both presynaptic and postsynaptic receptors [9,10]. It also highlighted the occurrence of adaptive changes in neurotransmitter systems. In the current view of depression pathogenesis, the involvement of the mechanisms of the so-called allostatic load, such as the lack of balance in the serotonergic, noradrenergic and dopaminergic systems, is emphasized. Serotonin is produced from tryptophan, an amino acid catabolized by indoloamine 2,3dioxygenase (IDO) [11]. The action of serotonin includes promoting neurogenesis via a stimulating effect on the production of brain-derived neurotrophic factor (BDNF). Thus, serotonin, through its neurotrophic activity, contributes to neuronal survival. A properly functioning serotonergic system produces serotonin from tryptophan. In the inflammatory reaction, depression develops with the involvement of pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a) and interferon-g (IFN-g) enzymes and activation of the kynurenine pathway indoloamine 2,3-dioxygenase responsible for tryptophan degradation [12]. The increased activity of these enzymes contributes to the shift of tryptophan from the pathway of serotonin production and to

increased synthesis of tryptophan catabolites (TRYCATs), quinolinic acid and kynurenine, in both serum and in the brain. Tryptophan catabolites and quinolinic acid, having cytotoxic effects, lead to degeneration of nerve cells in the hippocampus and destruction of postsynaptic elements of nerve cells, causing permanent damage of cognitive functions in patients with depression. The development of depression is also associated with a reduction in noradrenaline and dopamine production. Decreased density of NA neurons is induced by interferon-a (IFN-a), reflecting the pro-inflammatory and depressogenic interferon action in depression. In people with severe depression, decreased levels of homovanillic acid, a major metabolite of dopamine, was also found. This indicates the decrease of DA concentration in patients suffering from depression [13]. In the process of studying the development of depression, the neurophysiological and metabolic processes within neurons receiving information from the synapses through postsynaptic receptors were initially ignored. Much later, studies on the second messengers (G-proteins, protein kinase C, phosphatidylinositol cycle) involved in signal transduction within the neuron were carried out [14,15]. Studies highlighting the importance of the theory of disturbed equilibrium of cyclic adenosine monophosphate (cAMP), increased activity of the HPA axis and the presence of neuronal plasticity disorders in depression were also performed. Further studies on depression showed that development of depression is connected with endocrine changes. Among them we have the hypersecretion of corticotropin-releasing hormone (CRH), which in turn lead to distortion of mechanisms regulating adrenocorticotropic hormone (ACTH) secretion and cortisol [16,17]. The sensitivity of the glucocorticoid and mineralocorticoid receptors is decreased, which leads to the lack of clinical manifestations of adrenal cortex and medulla hyperfunction. Adrenal steroids, ACTH and CRH, have an impact on the metabolism of neurotransmitters. In this mechanism, cortisol decreases the availability of tryptophan, which is involved in serotonin synthesis. This results in a decreased level of serotonin in the brain of patient suffering from depression [18,19]. An increasing number of reports support the psychoimmunologic hypothesis that points to a link between the functioning of the central and autonomic nervous system, as well as endocrine and immunologic systems, in the pathogenesis of depression.

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Functioning of the neuroendocrine and immune systems in depression

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The structures of the immune system, the lymph nodes, thymus and bone marrow, have autonomic innervation and cell surface neurotransmitter receptors. The presence of nerve endings in the lymphoid organs and the presence of receptors for hormones and neuropeptides on immune cells is important due to the effect of cytokines on the neuroendocrine system [20,21]. In lymphoid organs, there are also cholinergic, noradrenergic and peptidergic nerve endings. Some of these endings look like the synapses between nerve fibers and lymphocytes [22]. In the literature, there are more than 30 types of receptors for hormones, neurotransmitters and neuropeptides described, which are located on leukocytes [23,24]. The presence of certain surface molecules typical of the immune system has been found in the central nervous system [25]. It has been shown that astrocytes have Fc receptors (FcR) and release interleukin-1 (IL-1), oligodendrocytes have CD8(+) T cells molecules and nerve cells have CD3(+) cells molecules. As mentioned earlier, prolonged stress affects the functioning of both the central and peripheral nervous system [26]. In depression, as in chronic stress, centers located in the hypothalamus and brainstem are activated. In these structures there are corticoliberin

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Please cite this article in press as: Ogłodek E, et al. The role of the neuroendocrine and immune systems in the pathogenesis of depression. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2014.04.009

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secreting neurons of the parvocellular red nucleus, neurons of the magnocellular nucleus and parabrachial nucleus of medulla oblongata and locus coeruleus, neurons secreting the antidiuretic hormone, vasopressin (arginine vasopressin – AVP) and hypothalamic paraventricular nuclei together with noradrenergic cells in the medulla oblongata, the pons and the locus coeruleus [27–29]. Undoubtedly the hypothalamic-pituitary-adrenal system plays the biggest role in stress and the main neurotransmitters of stress response are: corticotropin-releasing hormone, vasopressin, endorphins, glucocorticoids and catecholamines (adrenaline and noradrenaline) [30]. In depression, activation of the dopaminergic fibers of the mesocorticolimbic pathway (the reward system), the amygdala and hippocampus and the arcuate nucleus system takes place [31,32]. Serotonin and acetylcholine-induced release of corticoliberin is inhibited by brain neuropeptides, inhibitors of g-aminobutyric acid (GABA) synthesis and adrenal corticosteroids. The peripheral elements of the hypothalamic-pituitary-adrenal axis together with the whole sympathetic and parasympathetic systems and the adrenal medulla constitute the peripheral component of the nervous system. According to numerous studies, corticoliberin acts as the regulator of the hypothalamic-pituitary-adrenal axis [33]. Vasopressin, which also stimulates ACTH secretion, interacts with the corticotropin-releasing hormone. In physiological situations, in the absence of stress, CRH and AVP are secreted in pulses to the pituitary portal system. Its secretion is increased in the morning and decreases in the evening and at night. This is reflected by a morning peak of secretion of ACTH and cortisol. ACTH causes an increased secretion of cortisol and androgens, as well as aldosterone. This physiological mechanism is significantly impaired during chronic stress [34]. During a depressive episode, activation of the hypothalamic-pituitary-adrenal system, as well as the sympathetic and parasympathetic systems, occurs. Activity of the amygdala in the brain increases and the activity of the hippocampus decreases, which is responsible for disruption of the negative feedback mechanism of glucocorticoids. During depression, increased secretion of AVP and CRH to the pituitary portal system and anastomoses of the vascular system to the posterior pituitary is observed. As a result of these changes, there is an elevated concentration of corticotropine releasing factor (CRF) in the cerebrospinal fluid, an impaired pituitary response to CRF, increased plasma cortisol, a reduction in the number and sensitivity of glucocorticoid receptors and reduced feedback inhibition of the ‘stress axis’. Glucocorticoids, acting as the effector arm of the HPA axis, interact with CRH and ACTH in the negative feedback system, inhibiting their secretion. In a depressive episode, increased cortisol secretion following stimulation of the HPA axis affects the immune system, resulting in stimulation of cytokine and chemokine receptors. The persisting increase in activity of the endocrine and immune systems contributes to the production of pro-inflammatory cytokines which are mediators of allostasis, which leads to the establishment of a new equilibrium level to achieve allostasis [35].

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Inflammatory activation of the immune system in depression

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Development of depression is associated with the activation of adaptive systems in the body (allostatic), allowing for the introduction and maintenance of a new state of equilibrium (allostasis) in response to destabilizing pathogenetic factors. In this process, the immune system is involved and its disorder results in the impairment of the innate and acquired immunity associated with inflammatory activation of the immune system. Mechanisms of cellular and humoral immunity play a special role [36,37]. The organism’s response to the inflammation that occurs in depression, depends on the possibility of recognition and the

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ability to initiate the reaction, which leads to neutralization of harmful factors [38,39]. Neutrophils are the first line of defense against inflammation. Stimulating factors ( granulocyte-macrophage colony-stimulating factor – GM-CSF, granulocyte-colony stimulating factor – G-CSF) and IL-3 drive their differentiation in bone marrow from a common monocyte and macrophage progenitor cell. Neutrophils are responsible for forming the first line of defense against adverse external factors. Vasodilatation, increased vascular permeability and an increase in blood supply also occur during the inflammatory reaction. As a result of this process, various plasma proteins with protective functions, such as antibodies or proteins of the complement system, may reach the affected tissue. Mast cells, dendritic cells and macrophages, which phagocytize and secrete mediators of inflammation, are activated. Neutrophils constitute the circulating and marginal pools in the peripheral blood. During inflammation glucocorticoids activate neutrophils to move from the marginal to the circulating pool [40]. Subsequently, neurophiles migrate from the bloodstream into the inflamed tissue. The mediators of inflammatory reactions cause local vasodilation and the appearance of adhesion molecules on endothelial cells. This leads to the migration of leukocytes that continue phagocytosis and are subsequently phagocytized by macrophages. Infiltrating natural killer (NK) cells destroy pathogens and secrete interferon, which leads to the activation of macrophages, antigen presentation and the activation of mechanisms of specific immunity through T helper (Th)-1 cell. In inflammation, leukocytes infiltrate in several stages: margination, rolling, activation, tight adhesion and diapedesis. In the process of margination, leukocytes are pushed out from the main bloodstream toward the blood vessel wall. Then leukocytes come into contact with the endothelium of vessel wall and are subjected to rolling [41,42]. This process occurs by temporary binding of leukocyte receptors with selectins. However, the pressure of plasma and other cells flowing out of the vessel in the endothelium causes breaking of connections and the cell is slightly rotated. The binding of other receptors with the selectins makes the whole process repeat and the leukocyte begins to roll on endothelium. The phenomenon of the rolling of lymphocytes enables cell activation. Activation occurs when the leukocyte meets particular substances, otherwise, the leukocyte detaches from the endothelium and returns to the bloodstream to continue circulating in the body [43]. The most important activating substances are chemokines, which play an important role in diapedesis as well. The name ‘chemokine’ denotes the family of low molecular weight secreted proteins with the activity of chemotactic cytokines. Chemokines me be produced in the brain by infiltrating T cells, macrophages, astrocytes, microglia and the endothelium of brain vessels. As in cases of selectins, leukocytes must have receptors for chemokines, which exist on endothelium. As different populations and subpopulations of white blood cells have different receptors for chemokines, this is probably the most important step of leukocytes’ selection in the inflammation. The type of chemokines present on the surface of the endothelium depends largely on the nature of the antigen triggering the inflammatory reaction. Thus, at the stage of activation, a decision on the selection of the mechanism of pathogen removal is made. As a consequence of activation, the architecture of the leukocyte is changed, which results in a rapid change of cell shape, from almost spherical to flat and firmly adhered to endothelium [44]. This way, the leukocyte is no longer exposed to the strong bloodstream and it stops rolling. This step is called close adhesion and is possible due to the connection of the leukocyte surface integrins to their ligands on the surface of endothelial cells. In the last stage of diapedesis, leukocytes pass through the endothelial barrier and migrate through the tissue to the site of a pathogen. The movement of

Please cite this article in press as: Ogłodek E, et al. The role of the neuroendocrine and immune systems in the pathogenesis of depression. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2014.04.009

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leukocytes is a directed migration (called chemotaxis) toward the increasing gradient of chemotactic molecule concentration. The impairment of neutrophil chemotaxis is caused by lower serum concentration levels of chemotactic factors, including complement components, and impaired production of chemotactic factors, such as chemokines, by monocytes and neutrophils. The reduced bone marrow reserve of neutrophils and lower enzymatic activity are believed to be the main risk factors of inflammation in the pathogenesis of depression [45]. Cytokines associated with Cell-Mediated Immunity (CMI), e.g., IFN-g, can activate IDO, which leads to a reduction of tryptophan and serotonin concentrations, increased synthesis of tryptophan catabolites, and increased concentrations of quinolinic acid and kynurenine in the plasma and brain. In depression, IDO activation, a decrease in tryptophan levels, an increase in toxic TRYCATs and/ or a reduction in the neuroprotective TRYCATs such as kynurenic acid, take place. Some TRYCATs contribute to increased oxidative stress (e.g., 5-hydroxyanthranilic acid, 3-hydroxykynurenine, 3hydroxyanthranilic acid and quinolinic acid), taking part in the processes that facilitate neuroprogression and neurodegeneration. Furthermore, TRYCATs such as kynurenic acid, 3-hydroxyanthranilic acid and/or 3-hydroxykynurenine worsen mitochondrial energy metabolism, including the production of adenosine triphosphate, and contribute to the reduction of mitochondrial respiration. IFN-g released in the inflammatory response increases the activity of neurotoxic TRYCATs by inducing IDO. The cytotoxic activity of TRYCATs leads to degeneration of nerve cells, hippocampal cell death and reduction of central cholinergic action. All these mechanisms potentially enhance neuroprogression [46,47]. Scientific studies have shown that the titers of antiserotonin antibodies are significantly higher in patients with major depressive disorder (MDD) (54.1%), especially in those with melancholia (82.9%) compared with the control group (5.7%). Autoimmune responses may interfere with 5-HT neurotransmission, which explains the poor reactivity of serotonin in depression. As a result, the process of neurogenesis is significantly inhibited. Importantly, autoimmune activity directed against 5-HT is significantly associated with the number of previous depressive episodes. Patients who had more than 3 depressive episodes showed a higher frequency of autoimmunization against 5-HT than patients with 1 or 2 episodes. These results prove that each depressive episode increases the likelihood of developing acute autoimmune response directed against serotonin. The risk of subsequent depressive episodes and neuroprogression is also increased. To summarize, the above results indicate that the autoimmune response directed against 5-HT leads to sensitization or so-called kindling in the development of depression [48]. Although the adaptive mechanisms have protective effect, there is a cost to the organism associated with the reorganization of internal parameters, especially when the allostasis state is prolonged as a result of the persistence of the adverse effects of pathogenetic factors. Manifestation of negative health effects (development of depression) due to this process is known as allostatic load [49].

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The role of chemokines in the pathomechanism of depression

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The concept of allostasis became the theoretical basis for the creation of the latest model of stages in the course of depression, which is the concept of staging proposed by Brazilian researchers under the leadership of Flavio Kapczinski. It describes the disease in five consecutive stages from milder stages to severe and more resistant to treatment. The development of the disease is presented as an accumulation of allostasis process and allostatic load, resulting from exceeding the body’s adaptive abilities and progress of physiological changes that lead to the subsequent emergence of

negative clinical and biological effects. One of the biomarkers of staging are chemokines, mediators of allostasis, providing information on the progress of the disease process [50,51]. The basic role of chemokines is the recruitment of leukocytes is to maintain normal functioning of the immune system [52,53]. In the central nervous system, chemokines are present in both normal physiological and pathological conditions. They affect cells interactions, neuromodulation and synaptic transmission in depression. The two groups of chemokines and their receptors are proinflammatory and lymphoid (homeostatic, constitutive), which have been distinguished on the basis of their function in immunity [54]. Lymphoid cytokines (including SDF-1-stromal cellderived factor-1/CXCL12 chemokine) are secreted in different areas of lymphoid tissues and take a part in the nesting of immune cells in their places of maturation, ‘guiding’ the cells in haematopoiesis in bone marrow. Induced proinflammatory chemokines (e.g., RANTES-regulated on activation, normal T-cell expressed and secreted/CCL-5; SDF-1 chemokine) are produced by tissues and leukocytes in response to proinflammatory cytokines (IL-1, TNF-a, interferons). These chemokines disturb serotonin synthesis through the activation of indoloamine-2-3-deoxygenase, the enzyme necessary for a degradation of tryptophan to quinolinic acid [55]. Consequently, a deficiency of tryptophan, which is essential for serotonin synthesis, occurs. This result in a deficit of serotonin in the brain of depressed patients. The main role of chemokines is the recruitment of leukocytes to the site of inflammation. The modulation of integrin expression through chemokines may facilitate the migration of monocytes to the site of inflammatory focus. Chemokines are involved in immune development and inflammatory reactions after stimulation by cytokines by inducing chemotaxis of cells toward the site of inflammation [56]. Infiltration of leukocytes from blood into tissues is the process of interaction of leukocytes and endothelial cells. The main stimulators of chemokine production are the proinflammatory cytokines Il-1, TNF-a, IFN-g and the products of Th1 and Th2 cells, which may stimulate their secretion along with Il-1 and TNF-a. monocyte chemoattractant protein-1 (MCP-1/ CCL2) and RANTES chemokines induce CD11b, CD11c and CD18 cells molecules expression on monocytes [57,58]. Monocyte/ macrophage activation leads to the release of different factors (over 120 have been identified), including interleukins (IL) (IL-1, IL6, IL-12), TNF-a and -b interferons (IFN-a and -b) and growth factors like platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), arachidonic acid metabolites (prostaglandins, leukotrienes), platelet activating factor (PAF), complement components (C1-C5, B and D factors, properdin), coagulation factors (V, VII, IX, X, prothrombin) and proteases [6,59,26]. The release of these factors by monocytes has been described in scientific publications by many authors [60–62]. Reports on the influence of depression on IL-6 levels in serum are also numerous. However, scientific publications concerning the release of chemokines in depression are less numerous. Such studies have been conducted by Sutcigil et al. [63], Rajagopalan et al. [64] and Motivala et al. [65]. These authors measured the concentration of MCP-1 and IL-6 chemokines in men suffering from severe depression. In another study, Shen et al. [66] measured the concentration of MCP-1, SDF-1 and RANTES chemokines in males with deep depressive episodes. They found an increase in chemokine concentration in depression and its decrease after treatment with antidepressants. Antidepressants have antiinflammatory properties affecting the levels of pro-inflammatory cytokines [1]. Studies have shown that initially elevated levels of

Please cite this article in press as: Ogłodek E, et al. The role of the neuroendocrine and immune systems in the pathogenesis of depression. Pharmacol Rep (2014), http://dx.doi.org/10.1016/j.pharep.2014.04.009

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pro-inflammatory cytokines such as IL-12, IFN-g were reduced after treatment with drugs from the group of selective serotonin reuptake inhibitors (SSRI). SSRIs increase the concentration of antiinflammatory cytokines (e.g., IL-10, IL-4, tumor necrosis factor-b1) in the serum of patients suffering from depression [42]. Moreover, these drugs, similarly to antidepressants with other mechanisms of action, affect the expression of genes encoding neurotrophins, which are associated with mechanisms of synaptic plasticity. Pharmacogenetic studies have shown an association of a polymorphism of the gene encoding BDNF with the effect of treatment with fluoxetine. BDNF affects the development of serotonergic, noradrenergic and dopaminergic neurons [36]. Furthermore, BDNF is associated with membrane tyrosine-kinase-B receptor (TrkB). This leads to activation of complex intracellular signaling pathways. Studies performed in rats and mice showed that prolonged administration of selective serotonin-norepinephrine reuptake inhibitors (SNRI) increases the expression of BDNF and its trkB receptor in the hippocampus. In other experimental studies, changes in the behavior of animals after direct administration of BDNF to certain limbic structures were evaluated [39,38]. Even after a single infusion of this neurotrophin, changes in the animal’s behavior persisting 10 days could be observed, similar to those observed with long-term use of antidepressants. Moreover, studies concerning patients with depression have demonstrated that serum levels of BDNF in patients treated with antidepressants increased, while in untreated patients remained decreased. It was also found that there is a relationship between the level of BDNF and the severity of depression [67,68,47]. As severe depression develops as lower levels of BDNF are measured. Antidepressants used in patients suffering from depression demonstrate an antiinflammatory effect and can restore normal neurogenesis previously inhibited by stressful situations. In addition, they affect the proliferation of nerve cells and synaptic plasticity and are important factors of neuroprogression and hippocampus development [69,70]. In summary, the relationship between chemotactic cytokines, which are mediators of allostasis and markers of inflammation in depression, and the risk of depression should be emphasized. Determination of the concentration of chemokines and their receptors may be an important indicator of activation of the immune system, which reflects the stage of depression-staging. Thus, routine determination of chemokine concentrations in patients can be very useful in determining the severity of depression, which allows for choosing the best therapeutic strategy.

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Funding

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This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Conflict of interest

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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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