Although inconsistent results have been reported, several cytokines have been suggested to be associated with depressive disorders. Relatively consistent findings showed an increase in several cytokines, including interleukin-6 (IL-6), interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) in patients with depressive disorder versus healthy controls (HCs)
[10][11][12][13][14][15]. An increase or decrease in certain cytokines also reportedly affects treatment outcomes with antidepressants
[14][16][17]. In the association between the neuroimmune system and depressive disorder, interest has increased in the role of brain-derived neurotrophic factor (BDNF) as well as cytokines. BDNF is a neurotrophin that regulates neurogenesis, neuronal maturation, survival, and synaptic plasticity
[18][19]. Several previous studies have suggested that BDNF affects neuroimmune regulation in psychiatric disorders, including schizophrenia, mood disorders, and obsessive disorder
[20][21][22]. We discuss each in more detail in the following sections.
2.1. The Cytokines in Neuroinflammation
Neuroinflammation is defined as the reactive state of astrocytes and microglia, induced by pathological conditions
[23]. These cells mediate the immune responses in the brain by producing and secreting pro-inflammatory cytokines that are known to be associated with depressive disorder
[24][25]. The secretion of peripheral cytokines increases in pathologic states, such as infection, and affects hypothalamic-pituitary-adrenal (HPA) axis activation. Cytokines are a family of polypeptides that are important in cell signaling, and they affect the behavior of cells. Cytokines can access the brain by passing through leaky regions in the blood-brain barrier. They have functions such as neuroprotection and neurodegeneration in the central nervous system (CNS). They also have significant effects on neurotransmitters such as dopamine and serotonin
[26][27]. Mae et al. showed that the activity of IL-6 was higher in patients with depressive disorder than in controls. In the same study, increased IL-6 activity was related to hyperactivity of the HPA axis as well as high plasma cortisol levels
[16][28]. Since then, the number of studies on the relationship between cytokines and depressive disorder has increased. These studies have investigated several markers including IL-1, IL-1β, IL-6, IL-8, IL-10, TNF-α, interferon-γ (IFN-γ), and CRP
[29]. Cytokines are generally divided into pro-inflammatory and anti-inflammatory cytokines
[30]. Pro-inflammatory cytokines, including IL-1β, IL-6, IL-12, TNF-α, and IFN-γ, are thought to be associated with depressive disorders
[11][14][15][17][27][31][32][33]. Additionally, IL-6 and TNF-α negatively impact serotonin production and integrity
[34], which may increase the risk of depression. Furthermore, the release of TNF-α, as well as IL-1β, is thought to induce synaptic pruning. This leads to impaired neuroplasticity and structural brain changes that negatively impact cognition
[34][35]. CRP is an acute-phase protein that is released in response to inflammation and increases cytokine levels
[36][37]. Evidence of an association between inflammatory cytokines and the pathophysiology of depressive disorder has been reported; however, the direction of this association remains unclear.
Table 1 summarizes the previous studies of cytokines in pediatric depressive disorder.
Cross-sectional and longitudinal studies have been conducted on the relationship between pediatric depression and inflammatory markers
[10][11][12][13][14][17][38][39]. The cytokines that have been studied in pediatric depression are IL-1, IL-1β, IL-2, IL-6, IL-10, TNF-α, and IFN-γ. Gabbay et al. measured the plasma levels of IL-1β, IL-6, IL-10, TNF-α, and IFN-γ in adolescents with depressive disorder as well as in HCs
[10]. This study showed that plasma IFN-γ levels were significantly higher in the patient group than in the healthy control group. The same results were also found in non-medicated patients with MDD compared to HCs. Increased plasma IL-6 levels are among the most consistent findings in depression
[33][40][41]. Similar results were reported by a study of 42 female adolescents with depression, conducted by Blom et al.
[11]. Plasma levels of IL-6 and IFN-γ are associated with depression and anxiety symptoms’ severity. IL-6 levels were higher in the non-medicated patient group than in the medicated patient group. In addition to IL-6 and IFN-γ, IL-2, IL-10, and IL1-β levels were significantly higher in the patient group. In a meta-analysis of 22 studies (20,791 participants) of the association between depressive symptoms/depressive disorder and inflammation in children and adolescents, IL-6 level was correlated with depressive symptoms. Elevated IL-6 levels were evaluated as predictors of future depression
[41][42]. Evidence has also been gathered on the association between IL-6 level and internalizing disorder symptoms
[35][43]. In a study of 134 students (n = 76 with internalizing disorder, n = 58 without internalizing disorder) aged 10–17 years conducted by Cristiano Tschiedel Belem da Silva and colleagues in Brazil, students with internalizing disorders, including MDD, generalized anxiety disorder, separation anxiety disorder, social anxiety disorder, or panic disorder showed significantly higher IL-6 levels than students without an internalizing disorder
[12]. Internalizing behaviors evaluated at 8 years of age were associated with elevated IL-6 levels measured at 10 years of age in a large community cohort in England
[43]. Although there were no consistent results in pediatric depression, IL-1β levels were significantly associated with pediatric depression, and higher in MDD patients than in HCs
[11][13][33]. Pallavi et al. found that plasma levels of IL-1 β did not differ significantly between patients with MDD and controls. However, IL-1β levels are associated with anxiety symptoms’ severity in patients with MDD
[33]. In addition, the IL-1β level has been suggested to be related to treatment-refractory depression. Amitai et al. evaluated the plasma levels of IL-1β, TNF-α, and IL-6 in 41 adolescents aged 9–12 years with depressive and/or anxiety disorders
[17]. IL-1β, TNF-α, and IL-6 levels were high in the selective serotonin reuptake inhibitor (SSRI)-refractory patient group. This suggests the possible predictability of resistance to fluoxetine treatment in children and adolescents.
TNF-α is also reportedly highly relevant in pediatric depression. In previous studies of adult and pediatric depression, plasma levels of TNF-α levels showed mixed results. However, treatment with cytokines, including TNF-α, reportedly induces depressive symptoms
[44][45][46]. Plasma levels of TNF-α did not differ significantly or were increased in patients with MDD versus controls
[10][11][13][14][38][39]. However, a decrease in plasma TNF-α levels after antidepressant treatment in patients with MDD was reported
[13][17]. In these studies, a statistically significant decrease in plasma TNF-α levels was reported 4 and 8 weeks after antidepressant drug treatment, respectively. Studies have examined the relationship between TNF-α level and childhood trauma. The relationship between childhood trauma and blood TNF-α level is reportedly unclear
[47][48]. Peters et al. reported that TNF-α was associated with reduced inhibitory control performance in adolescents with depression and childhood trauma
[38]. Rengasamy et al. suggested that higher baseline levels of TNF-α are associated with greater depression and anhedonia symptoms’ severity. They found that a higher baseline TNF-α level affects the depressive trajectory
[39]. In a meta-analysis conducted by D’Acunto et al. on pediatric depression (despite including a small number of studies), the mean TNF-α level was higher in the MDD patient group than in the healthy control group
[49]. On the other hand, Gabbay et al. reported that suicidal adolescents with MDD showed lower plasma TNF-α levels than non-suicidal adolescents with MDD. Therefore, further research on TNF-α level is required
[32]. The relationship between CRP and pediatric depression has not been clearly identified, and contradictory results have been reported. Chaiton et al. found no significant association between depressive symptoms and serum CRP levels after the adjustment for variables such as body mass index, smoking, and blood pressure
[50]. In a study by Copeland et al., CRP levels did not predict later depression. However, cumulative depressive episodes were suggested to affect later CRP levels
[37]. On the other hand, Miller and Cole reported that the transition to depression in adolescents previously exposed to childhood adversity was accompanied by increased CRP levels
[51]. In this study, CRP levels remained high in adolescents with depression and childhood adversity, even 6 months after the depressive symptoms improved. This suggests a relationship between childhood adversity and the neuroinflammatory system. In a study of Iranian female adolescents, Tabatabaeizadeh et al. showed a higher mean CRP level in the depressive disorder group, while serum CRP levels were positively associated with depressive symptoms’ severity
[52]. In a meta-analysis by Colasanto et al., a significant association between CRP levels and depression was observed, although causality could not be inferred
[41].
Similar to the previous cytokine study of adults, increased levels of IL-6 were found in cases of pediatric depression and decreased after treatment. In addition, increased IL-6 levels in pediatric depression are associated with adverse childhood experiences (ACEs). In a previous study, depressed patients with ACEs had increased IL-6 levels compared to depressed patients without ACEs in adults, which suggests the possibility that an increased IL-6 level may be a change seen in the MDD risk group and patients with early-stage MDD
[53]. TNF-α levels were increased in cases of pediatric and adult depression, but the response to treatment differed. Although TNF-α tends to decrease after medication treatment in pediatric depression, an increase in TNF-α level was observed after treatment in adult depression
[54]. It is possible that the underlying pathophysiology of depression differs between adolescents and adults, and future studies controlling other variables such as medication exposure and ACEs are needed.
Table 1. Previous studies of cytokines in pediatric depressive disorder.
Study |
Objective |
Design |
Inflammatory Markers |
Findings |
Gabbay et al., 2009 [10] |
To examine the immune system in adolescents with MDD |
N: 45, age 12–19 years; 13 psychotropic-free MDD Pts, 17 MDD Pts with medication, and 15 HCs |
Plasma IL-6, IFN-γ, TNF-α, IL-4, and IL-1β |
Significantly higher levels of plasma IFN-γ in MDD Pts and trend for IL-6 to be elevated in MDD group; Significantly increased level of IFN-γ in the unmedicated MDD group compared to HCs |
Henje Blom et al., 2011 [11] |
To investigate the effects of antidepressants on cytokines in adolescent females with anxiety disorder and/or depressive disorder |
N: 102, age 14.5–18.4 years; 42 Pts (26 unmedicated Pts and 16 SSRI Pts) and 60 HCs |
Plasma IL-1β, IL-2, IL-6, IL-10, TNF-α, and IFN-γ |
Significantly higher values of IL-2, IL-10, and IL1-β in patient group; higher level of IL-6 in the non-medicated subgroup compared to the medicated subgroup; higher levels of IL-6 and IFN-γ were significantly related to more severe self-assessed symptoms of anxiety and depression |
Copeland et al., 2012 [37] |
To test (1) the effect of CRP levels on later depression status; (2) the effect of depression status on later CRP levels; and (3) the effect of cumulative depressive episodes on later CRP levels. |
N: 1420, age 9, 11, and 13 years at intake; longitudinal study with annual assessment to age 16 and again at 19 and 21 years |
CRP (dried blood spot) |
CRP levels were not associated with later depression status; Cumulative depressive episodes predicted later CRP levels |
Rengasamy et al., 2012 [39] |
To examine the associations of IL-6 and TNF-α with depression severity and anhedonia severity |
N: 36, age 12–18 years; 36 adolescents with depressive disorder, cross-sectional and longitudinal study |
TNF-α, and IL-6 |
Baseline TNFα was positively associated with baseline and follow-up SHAPS anhedonia scores, and follow-up CDRS-R |
Amitai et al., 2016 [17] |
To determine whether plasma levels of pro-inflammatory cytokines can predict response to treatment and/or are altered post fluoxetine treatment in children and adolescents. |
N: 41, age 7–18 years; children and adolescents with depression and/or anxiety disorders. |
Plasma IL-1β, IL-6, and TNF-α |
Significantly higher levels of pro-inflammatory cytokines in SSRI-refractory than in SSRI-responsive Pts; TNF-α levels significantly reduced after 8 weeks of antidepressant treatment |
da Silva et al., 2017 [12] |
To compare serum levels of IL-6 and IL-10 between non-medicated adolescents with internalizing disorders and a comparison group of adolescents without internalizing disorders |
N: 134, age 10–17 years; 76 adolescents with internalizing disorder and 58 adolescents without internalizing disorder |
Plasma IL-6, and IL-10 |
Adolescents with internalizing disorders had significantly higher levels of IL-6 as compared to those without internalizing disorders |
Pérez-Sánchez et al., 2018 [13] |
To detect (1) the alterations in the cytokine profiles of adolescents during 8 weeks of treatment with fluoxetine and (2) the correlation between symptomatology and inflammatory profiles |
N: 40, age 14–19 years; 22 adolescents with first episode of MDD and 18 HCs, cross-sectional and longitudinal study |
Plasma IL-2, IFN-γ, IL-1β, TNF-α, IL-6, IL-15, IL-10, IL-5, IL-13, IL-1Ra, and IL-12p70 |
Significantly increased levels of pro-inflammatory cytokines (IL-2, IFN-γ, IL-1β, TNF-α, IL-6, IL-12, and IL-15) and anti-inflammatory cytokines (IL-4, IL-5, and IL-13) in MDD Pts; IFN-γ, IL-1β, TNF-α, IL-6, IL-12, and IL-15 decreased only at week 4; increased IL-2 only at week 8; increased anti-inflammatory cytokines IL-4 and IL-5 at week 8 |
Peters et al., 2019 [38] |
1. To compare groups with inflammation 2. To evaluate associations between inflammation and inhibitory control |
N: 70, age 12–17 years; 22 depressive adolescents with childhood trauma (DEP-T), 18 depressive adolescents (DEP), and 30 HCs |
Plasma IL-1β, TNF-α, IL-6 |
Significantly elevated levels of IL-6 in both DEP and DEP-T relative to HCs and significantly elevated levels of TNF-α in DEP; No group differences were detected in IL-1β; TNF-α was associated with behavior-based and observer-rated inhibitory control deficits |
Lee et al., 2020 [14] |
1. To examine (1) the difference between inflammatory markers in MDD Pts and HCs and (2) whether these changes would be altered following antidepressant treatment 2. To investigate the relationship between cytokines’ level with the severity of depression |
N: 50, age 13–18 years; 25 medication-naïve MDD Pts and 25 HCs, cross-sectional and longitudinal study |
Plasma IL-1β, IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ |
MDD Pts had significantly decreased level of plasm IL-2, IFN-γ, TNF-α, and IL-10 compared to healthy controls; IL-2, IFN-γ, and IL-10 showed significant increases after 12 weeks treatment compared to before treatment. IFN-γ level was negatively correlated with the CDI (r = −0.377, p < 0.01) and HDRS score (r = −0.457, p < 0.01) |