Major depressive disorder (MDD) is one of the most prevalent mental illness and a leading cause of disability worldwide. Despite a range of effective treatments, more than 30% of patients do not achieve remission as a result of conventional therapy. In these circumstances the identification of novel drug targets and pathogenic factors becomes essential for selecting more efficacious and personalized treatment. Increasing evidence has implicated the role of inflammation in the pathophysiology of depression, revealing potential new pathways and treatment options. Moreover, convergent evidence indicates that MDD is related to disturbed neurogenesis and suggests a possible role of neurotrophic factors in recovery of function in patients. Although the influence of antidepressants on inflammatory cytokines balance was widely reported in various studies, the exact correlation between drugs used and specific cytokines and neurotrophins serum levels often remains inconsistent. Available data suggest anti-inflammatory properties of selective serotonin reuptake inhibitors (SSRIs), selective serotonin and noradrenaline inhibitors (SNRIs), and tricyclic antidepressants (TCAs) as a possible additional mechanism of reduction of depressive symptoms.
- depression
- inflammatory cytokines
- response to antidepressants
1. Depression and Markers
Depression is the most commonly diagnosed psychiatric disorder. It has a multifactorial etiology and the various hypotheses of depression are complementary to one another. Major depression has been associated with symptoms of immune activation, the phenomenon of oxidative stress, changes in immune processes, and activation of the inflammatory response system (IRS) [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Recognized markers of inflammation include: inflammatory enzymes, pro-inflammatory cytokines, and anti-inflammatory cytokines.
Studies suggest that depression is associated with elevated levels of both pro-inflammatory and anti-inflammatory cytokines, e.g., IL-1β, IL-6, IFN-γ, TNF-α, and C-reactive protein (CRP). Cytokines are a diverse group of biochemical compounds produced by immunocompetent cells of the immune system: lymphocytes, macrophages, and natural killer (NK) cells. The inflammatory hypothesis of depression, also referred to as the cytokine hypothesis, suggests that pro-inflammatory cytokines, acting as neuromodulators, affect the neurochemical, behavioral, and neuroendocrine features of depression [3][4][13][14][15]. Pro-inflammatory cytokines may cause hypothalamic–pituitary–adrenal (HPA) axis hyperactivity by interfering with the negative feedback of the HPA axis and corticosteroids (CS) and may reduce serotonin (5-HT) levels by decreasing the availability of its precursor, tryptophan (TRP), through the activation of a TRP-metabolizing enzyme, indoleamine 2,3-dioxygenase (IDO) [3][4][8][14][15][16][17]. Excessive HPA-axis activity and immune dysregulation also lead to abnormal function of the kynurenine pathway responsible for tryptophan conversion to two key compounds involved in mood regulation: serotonin and melatonin [16]. According to the kynurenine hypothesis of depression, inflammatory factors cause excessive activation of IDO, an enzyme found in microglia, astrocytes, and neurons [14][15][16]. Depression is therefore associated with neuro–immuno–metabolic interactions and immunometabolic dysregulation.
2. Inflammatory Cytokines
Studies confirm that depressive disorders, in the absence of other physical comorbidities, are associated with increased levels of various pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interleukins (ILs). According to the cytokine hypothesis of depression proposed by Maes, markers of inflammation play the key role in the development of depressive symptoms [1][2]. Cytokines are most commonly classified according to their effects on inflammation into cytokines that stimulate the development of inflammation, i.e., pro-inflammatory cytokines (e.g., interferon (IFN)-γ, TNF, IL-1, IL-2, IL-5, IL-8) and those that suppress inflammation, i.e., anti-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α, IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, IL-29). There is also a group of cytokines categorized as either anti- or pro-inflammatory, depending on the circumstances (e.g., IL-6, TGF-β, INF-α).
3. Interferon Gamma (IFN-γ)
Interferon gamma (IFN-γ) is a pro-inflammatory cytokine produced by immune cells, principally Th1 cells, cytotoxic lymphocytes, B cells, and antigen-presenting cells. IFN-γ induces indoleamine 2,3-dioxygenase (IDO), which catalyzes conversion of tryptophan to kynurenine in the kynurenine pathway. This reaction results in decreased serotonin levels and overactivity of the glutamatergic system, which have been linked to depressive symptoms [3][4][13][14][15][16][18]. Given the evidence suggesting the potential involvement of IFN-γ in the pathogenesis of MDD, this cytokine has been investigated in numerous studies. The present review included studies that assessed the effects of treatment of MDD patients with venlafaxine, paroxetine, duloxetine, and sertraline on IFN-γ.The results concerning the effect of these antidepressant drugs on IFN-γ levels obtained by the respective research teams and presented in this review are conflicting.
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Table 1.
| Study | Publication Year | Number of Patients | Duration of the Study | Markers | Medications | Influence of Drugs on Markers | Results |
|---|
| Fornaro et al. [23] | 2013 | N = 30 | 6 weeks, 12 weeks | IL-1b, IL-2, IL-4, IL-10, IL-12, IFN-g, TNF-α | duloxetine | NO | 6 weeks of treatment: no significant variations in mean cytokine plasma values; in early responders (ER) TNF-α levels decreased; in non-responders (ENR) IL-10 values decreased and IL-1b, IL-12, and IFN-g levels increased. Compared with controls, ER showed lower levels of IFN-g and TNF-α while ENR showed lower levels of IFN-g and IL-1b. 12 weeks: ENR—lower levels of IL-1b, IFN-g, and TNF-α compared with controls. |
| Wang et al. [24] | 2019 | N = 123 | meta-analysis | IL-1β, IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ | escitalopram, citalopram, sertraline, fluoxetine, fluvoxamine, paroxetine | NO | Non-significant treatment effect. |
| Więdłocha et al. [25] | 2017 | N = 154 | meta-analysis | IL-1ß, IL-2, IL-5, IL-6, IL-8, IL-10, CRP, TNF-α, IFN-γ | escitalopram, citalopram, sertraline, fluoxetine, fluvoxamine, venlafaxine, duloxetine, paroxetine, amitriptiline, clomipramine, nortriptiline, mirtazapine | NO | There was no statistically significant effect of antidepressant treatment on cytokines levels. |
| Köhler et al. [26] | 2017 | N = 242 | meta-analisys | IL-6, TNF-α, IL-1b, IL-10, IL-4, IFN-y, IL-2, IL-8, CCL-2, CCL-3, IL-13, IL-17, IL-5, IL-7, IL-1R, sIL-2 receptor | escitalopram, citalopram, sertraline, fluoxetine, fluvoxamine, paroxetine, venlafaxine, duloxetine | NO | Levels of cytokine/chemokines were not significantly altered after antidepressant drug treatment. |
| Chen et al. [19] | 2018 | 91 were completers for 8-week paroxetine (n = 50) or 8-week venlafaxine treatment (n = 41) | 8 weeks | IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL5, IL-6, IL-8, IL-10, and GM-CSF | venlafaxine, paroxetine | IFN-y YES Venlafaxine: IL-5, IL-8 YES; IL-1 NO Paroxetine: IL-4 NO |
8 weeks of treatment: venlafaxine—the mean IFN-γ, TNF-α, IL-4, IL-5, and IL-8 levels were significantly lower than in the paroxetine-treated group. Levels of the Th1 cytokines, IFN-γ, and TNF-α decreased after venlafaxine treatment, whereas IFN-γ and TNF-α increased after paroxetine treatment. Significant differences between paroxetine and venlafaxine treatment were observed in the change of cytokine levels such as IFN-γ, TNF-α, IL-4, IL-5, IL-8, and GM-CSF. After the 8-week paroxetine treatment, the mean IFN-γ and TNF-α levels increased in the ENR. IL-6 levels increased more in the ENR than in the ER. In the venlafaxine-treated group, the mean changes in cytokine levels did not differ significantly between ENR and ER. For levels of the Th2 and other cytokines, venlafaxine treatment caused a greater decrease in IL-4, IL-5, and IL-8 levels than did paroxetine treatment. After the 8-week venlafaxine treatment, the mean IL-1β and IL-8 levels had decreased and did not differ significantly from those of the healthy controls. The levels of IFN-γ and TNF-α increased after paroxetine treatment. |
| Dahl et al. [20] | 2014 | N = 50 | 12 weeks | IL-1b, IL-1Ra, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-15, G-CSF, MIP-1a, TNF-α, (IFNg) | sertraline, escitalopram, citalopram, venlafaxine, mirtazapine, benzodiazepines, lamotrigine, psychotherapy | YES | Seven of the nine cytokines that were elevated at baseline were significantly reduced after the 12 weeks of therapy compared with baseline: IL-1Ra, IL-6, IL-7, IL-8, IL-10, G-CSF, and IFNg. The levels of IL-1b and IL-5 were not significantly reduced. |
| Brunoni et al. [22] | 2013 | N = 18 | 6 weeks | IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF-α | sertraline | YES/no | The plasma levels of all cytokines (except TNF-α) decreased during the treatment. No significant results were found comparing cytokine plasma levels at baseline according to clinical response. |
| Hernandez et al. [21] | 2013 | N = 31 | 52 weeks | IL-1β, IL-2, IFN-γ, IL-4, IL-10, and IL-13 | fluoxetine, setraline, paroxetine | YES | IFN-γ levels fluctuated during the treatments and showed significant changes. Before treatment, patients had lower IFN-γ levels. At the end of treatment, IFN-γ levels were comparable with those of healthy volunteers. |
| Carboni et al. [27] | 2019 | N = 103 | 10 | IL-6, IL- 10, TNF-α, TNFRII, BDNF, CRP, MMP9, and PAI1 |
venlafaxine (51), paroxetine (52) |
YES | Paroxetine: increase in biomarker levels after treatment correlated with reduction in depression symptomatology for TNF-α, IL-6, IL-10, and CRP. Responders showed higher baseline IL-10 levels compared with non-responders. Venlafaxine—significant association between baseline levels of CRP and changes in HAM-D in males. |
| Manoharan et al. [28] | 2016 | N = 73 MDD patients (39 responders and 34 non-responders) | 6 | IL-6 | fluoxetine | NO | IL-6 levels were significantly higher in MDD patients when compared with controls. Pre-treatment serum IL-6 concentrations did not significantly differ between responders and nonresponders. Both groups also did not show significant reduction in the IL-6 levels post-treatment. A significant correlation was observed between the percentage change in IL-6 and percentage change in depression score in responders. |
| Jazayeri et al. [29] | 2010 | N = 14 | 8 | IL-1, IL-6 | fluoxetine | NO | Serum concentrations of IL-1β and IL-6 did not change significantly after intervention based on repeated-measures ANOVA. |
| Halaris et al. [30] | 2015 | N = 20 | 8 and 12 weeks | CRP, TNF-α, IL-1, IL-4, IL-6, IL-8, IL-10 | escitalopram | NO | Closer inspection of the averages indicates a tendency for some biomarkers to decline at week 8 but to bounce back up again at week 12 (e.g., IL-6, hsCRP, TNF-α). At 8 weeks of ESC monotherapy, when the HAM-D and related scores improved significantly, hsCRP, TNF-α, IL-6, IL-8, IL-10, and MCP1 trended lower. |
| Eller, et al. [31] | 2008 | N = 100 74 responders 45 HV |
4 and 12 weeks | IL-8, TNF-α | escitalopram | TNF—YES, The rest NO |
The comparison of baseline cytokine levels between responders, non-responders, and healthy subjects demonstrated statistically significant between-groups difference for TNF-α but not for other cytokines. Escitalopram: the concentration of TNF-α did not significantly change during 12 weeks of treatment; however, it increased to normal levels in the group of responders. Week 12, ANCOVA did not show differences in cytokine levels between treatment groups and healthy volunteers. |
| Chang et al. [32] | 2020 | N = 149 | 6 | CRP | venlafaxine (n = 76) fluoxetine (n = 73) | NO | The baseline CRP levels were significantly correlated with treatment response at week 2. Patients with higher CRP levels had a poorer treatment response. CRP level had increased significantly after six weeks of treatment in patients receiving either antidepressant. The CRP level remained significantly high after six weeks of treatment in patients with a higher baseline level. |
| Yang et al. [33] | 2019 | review | Raison et al. (2013) [7]—baseline values of hsCRP > 5 mg/L predicted a greater decrease in HAMD-17 scores in infliximab-treated patients than placebo-treated subjects. Papakostas et al. (2014) [34]—changes on the HAMD28 scoring list were significantly greater than baseline scores in a subpopulation with hsCRP levels above the study median value when comparing L-methylfolate with placebo treatment. Kruse et al. (2018) [35]—baseline CRP was not associated with changes of MADRS scores, but it was significantly correlated with the end-of-treatment scores for women. Chen et al. (2018) [19]—log-transformed CRP levels were not predictive for ketamine treatment response. |
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| Tuglu et al. [36] | 2003 | N = 26 | 6 | TNF-α, CRP | citalopram, sertraline, fluoxetine, fluvoxamine, paroxetine | YES | CRP levels after treatment were significantly lower than those on admission. Comparison of pre- and post-treatment measurements revealed that TNF-α, CRP, and leukocyte count decreased to levels comparable with those of the control subjects. |
p > 0.05) [24][25][26]. Most of the studies showed that IFN-γ levels were lower in patients with MDD before the initiation of treatment with antidepressant drugs [22][23], and these reports have been confirmed by a meta-analysis that compared pre-treatment results in MDD patients (
n = 154) with those in healthy individuals [25]. Chen et al. (2017) and Dahl et al. (2014) reported significantly increased levels of IFN-γ in untreated patients with depression [19][20]. This review shows that the results concerning IFN-γ levels before the treatment of MDD and after its initiation are equivocal and require further studies. Studies have shown increased INF-γ levels after treatment with duloxetine and paroxetine [19][23] and decreased IFN-γ levels after treatment with venlafaxine and sertraline [19][22]. Baseline IFN-γ levels in patients with MDD did not predict the response after 6 weeks of treatment [22].
4. Interleukin-1 (IL-1)
A significant role in the pathogenesis of depressive states is attributed to interleukin-1 (IL-1), which is important for the regulation of multiple brain processes, including sleep and food intake, which are disturbed in depression. IL-1 plays the role of a universal factor that stimulates inflammation and is produced in response to various types of antigens. It is also capable of stimulating cells to produce other pro-inflammatory cytokines [37]. The term “interleukin-1” refers to a whole group of cytokines that play a key role in initiating inflammation. Because of the similar biological activity and the same receptor involved in signal transduction, IL-1α (IL-1F1) and IL-1β (IL-1F2) are often described as just one IL-1. They do, however, differ, for instance, in terms of the cells in which they are synthesized. IL-1α is synthesized by monocytes, macrophages, neutrophils, lymphocytes, glial cells, keratinocytes, and endothelial cells, while IL-1β is mainly synthesized by monocytes/macrophages. Another difference is that IL-1β is synthesized in the form of a precursor (pro-interleukin-1β) that is converted to the mature form by caspase-1. IL-1β is secreted to blood and acts systemically. This cytokine also affects the activity of the HPA axis by means of a negative feedback relationship between IL-1β production and overactivity of the HPA axis, whose dysregulation may play a role in initiating and maintaining the clinical and biochemical manifestations of depression [38][39]. A total of six clinical studies were included in the analysis of the effects of antidepressant drugs on IL-1 levels.
In these studies, IL-1β levels were significantly higher at baseline in patients with MDD than those in healthy individuals [19][23][29][40][41]. Chen et al. assessed the effect of venlafaxine (
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p = 0.032). The levels of IL-1β in patients with a later response to the drug were lower than those in healthy individuals but subsequently increased after 12 weeks of treatment [23]. A lack of significant differences in the levels of IL-1β before and after treatment with fluoxetine has been reported by Jazayeri et al. [29]. The review of studies assessing the effects of antidepressant drugs on IL-1 levels shows that the results for IL-1 levels after initiation of treatment with those drugs are equivocal and require further studies. A significant increase in the secretion of IL-1β has been demonstrated in patients with depression. Varying levels of IL-1 have been reported depending on the drug used and the timing of measurements. There have been reports of no effect of antidepressant drugs on IL-1 levels [29][30], reports of decreased levels [19], and reports of increased levels [21][23][40] after treatment with antidepressant drugs. Patients achieving clinical improvement had higher IL-1β levels compared with those who had not achieved improvement with the treatment, and patients with a later response to the drug had lower IL-1β levels compared with those in healthy individuals [23].
5. Interleukin-6 (IL-6)
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p = 0.007) [43]. The review of the studies assessing the effects of antidepressant drugs on IL-6 levels revealed considerable discrepancies in study results. In all the studies included in the review, IL-6 levels in patients with MDD were significantly higher than those in healthy individuals [27][28][41][43], but the effects of the study drugs on IL-6 levels varied. These effects also varied depending on the timing of the second measurement of the IL-6 level. In a study by Manoharanet al. (2016), patients who favorably responded to the treatment did not differ in terms of pre-treatment IL-6 levels from non-responders [28], while in the study by Yoshimura et al. (2013), IL-6 levels were significantly higher in patients favorably responding to the drugs [43]. In patients responding to the treatment, IL-6 levels significantly decreased after treatment [27][41][43].
6. Interleukin-8 (IL-8)
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p = 0.118). Cytokine levels were measured at baseline and after 4 and 12 weeks of the experiment. No correlations between IL-8 and depression markers were observed [31]. Levels of IL-8 were either unaffected [30][31] or decreased [19][31] following antidepressant treatment with venlafaxine and sertraline. Two studies confirm the lack of effect on IL-8 levels by escitalopram [30][31].
7. Tumour Necrosis Factor (TNF)
Another mediator of inflammation that plays a significant role in the pathogenesis of depression is TNF-α, which is produced in small amounts by neurons and microglia. Elevation in plasma TNF levels is believed to play the role of a mediator in patients with depression compared with healthy individuals [44] (Almond, 2013). Most studies have reported elevated TNF levels in patients with MDD compared with healthy individuals [27][31][41][44]. However, Fornaro et al. (2013) did not observe any differences in pre-treatment TNF levels between healthy individuals (
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