Background
Cognitive deficits have been regarded as the core features of major depressive disorder (MDD) [
1‐
3]. Previous studies indicated that cognitive deficits of MDD mainly occurred in the following cognitive domains, such as memory, attention, visuospatial/constructional skills, language, executive function and processing speed [
2,
4‐
6]. Moreover, cognitive deficits may further influence treatment, rehabilitation, quality life, social activity, and even employment for MDD [
7]. Thus, cognitive deficits should be considered a potential target for the treatment and rehabilitation of MDD [
8‐
10]. However, the pathogenesis of cognitive deficits in patients with MDD is still not well understood and requires further investigation.
Interleukin 8 (IL-8) is an inflammatory cytokine synthesized and released by macrophages and brain microglia and astrocytes [
11,
12]. IL-8 may serve either pro- or anti-inflammatory role mainly depending on the concentration [
13]. An animal study has shown a higher expression level of
IL-8 gene in microglia and astrocytes of the hippocampus compared to other brain regions [
14]. Selective serotonin reuptake inhibitors (SSRIs) have been reported to modulate the ability of microglia and astrocytes to produce inflammatory cytokines [
15‐
20]. Altered activity of hippocampal microglia and astrocytes may contribute to cognitive deficits and be associated with the decline in cognitive performance in patients with MDD [
21]. Mounting evidence support that MDD is considered to be a neuroinflammatory disorder that is closely related to abnormal activation of microglia and astrocytes [
12,
22,
23]. Previous studies demonstrated the immunomodulating effects of SSRI treatment on MDD, further suggesting that SSRIs may possess anti-inflammatory properties [
24,
25]. Moreover, several studies have found that serum IL-8 influenced cognitive function in normal elderly subjects and patients with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) [
5,
26‐
30]. Thus, the above findings suggest that serum IL-8 may be implicated in regulating cognitive performance in MDD patients with the administration of SSRIs.
However, no studies have examined serum IL-8 levels in relation to cognitive function in MDD patients with SSRIs. Thus, the present cross-sectional study aimed to examine serum IL-8 levels, cognitive function, and their correlations in MDD patients with SSRIs.
Discussion
To our knowledge, this is the first cross-sectional study that investigated serum IL-8 levels, cognitive function, and their associations in MDD patients with SSRIs. This study had three major findings: 1) cognitive function was worse in MDD patients with SSRIs than in healthy controls; 2) serum log10IL-8 levels were nominally higher in MDD patients with SSRIs than in healthy controls; 3) serum log10IL-8 levels were positively associated with delayed memory and visuospatial/constructional sub-scores in MDD patients with SSRIs.
Increasing evidence from previous studies has supported that cognitive impairment is a core feature of MDD and it affects the treatment, rehabilitation, quality life, and even employment for MDD [
1‐
3,
7]. Thus, mitigating cognitive deficits should be the focus of MDD treatment [
8,
10]. Our data showed that all RBANS test scores were significantly lower in patients with MDD than in healthy controls, suggesting that MDD patients still exhibited poorer cognitive abilities even though they were treated with the SSRI antidepressants. This finding was supported by a recent study that reported significant differences in all RBANS test scores between 116 healthy controls and 90 MDD patients treated with anti-depressants (including 39 patients with SSRIs) [
6]. Several previous studies also demonstrated that there was a marked decline in the RBANS total score in MDD patients in comparison to healthy controls [
3,
36‐
39]. In addition, several recent studies reported that the SSRIs could improve cognitive function in patients with MDD [
10,
40]. Although patients with MDD were administrated oral single SSRI in the present cross-sectional study, our data did not support that SSRIs could achieve cognitive remission of MDD. Thus, a longitudinal and multicenter follow-up SSRI intervention study should be performed to validate the effect of SSRI treatment on cognitive performance of MDD in the future.
IL-8 was an inflammatory cytokine that was produced by macrophages and brain neuron cells such as microglia and astrocytes [
11,
12]. IL-8 may be implicated in the pathogenesis of psychiatric disorders and their treatment effect [
41]. Our finding showed that serum log
10IL-8 levels were nominally elevated in MDD patients with SSRIs than in healthy controls, which further suggest that higher IL-8 levels might be involved in the psychopathology of depression. Previous studies demonstrated that increased serum IL-8 levels were implicated in the underlying pathogenesis of MDD. For example, at the protein level, cerebrospinal fluid (CSF)/serum/plasma levels of IL-8 were significantly increased in patients with MDD in comparison to healthy controls [
42‐
46]. At the molecular level, a higher mRNA expression level of the
IL-8 gene (
IL-8, located on chromosome 4q) was reported in the prefrontal cortex of drug-free MDD patients compared to healthy controls [
47]. Moreover, the rs4078 polymorphism in
IL-8 was significantly associated with the susceptibility to MDD [
48,
49]. However, the mRNA and protein levels of
IL-8 were found significantly declined in patients with MDD in comparison to healthy controls [
50,
51]. In addition, several studies have reported that there were no significant differences in the protein and mRNA levels of
IL-8 between patients with MDD and healthy controls [
52‐
55]. These discrepant results may be due to the effects of a series of confounding factors, such as sex, age, BMI, age of onset, illness duration, antidepressant types and dosages, diet, sample size, and ethnicities.
SSRI antidepressants have been reported to activate microglia and astrocytes to synthesize and release inflammatory cytokines [
15‐
20]. Dysfunctional microglia and astrocytes in the hippocampus were implicated in cognitive deficits in individuals with brain disorders [
21]. The above evidence hinted that there might be significant associations among inflammation cytokines, cognitive function, SSRIs, and microglia and astrocytes. Intriguingly, our study found that serum log
10IL-8 levels were nominally elevated in MDD patients with SSRIs than in healthy controls, further suggesting that elevated IL-8 levels in patients with MDD might be modulated by SSRIs which activated the microglia and astrocytes of depression. Moreover, serum log
10IL-8 levels were positively associated with the sub-scores of RBANS delayed memory and visuospatial/constructional function in MDD patients with SSRIs, hinting that a higher concentration of serum IL-8 corresponds to improving MDD delayed memory and visuospatial/constructional by SSRIs modulating the activity of microglia and astrocytes to synthesize and release IL-8. This finding also indicated that elevated serum IL-8 levels might have neuroprotection to the brains of MDD [
56,
57]. Previous studies demonstrated that a decline in serum/plasma IL8 levels was implicated in cognitive impairment disorders including MCI and AD [
27,
29]. However, the neurotoxic effect of IL-8 on human brain function has also been reported. Increased serum IL-8 levels were involved in poor performance in memory, cognitive speed and motor function in normal elderly subjects [
26]. Thus, the effect of IL-8 on cognitive function of brain disorders might be complex, i.e., IL-8 has either neuroprotective or neurotoxic roles [
56,
58]. However, our finding has shown that elevated IL-8 levels might improve cognitive function in MDD patients following the administration of oral single SSRI. Thus, further longitudinal studies should be designed to explore the relationships among serum IL-8 levels, cognition, and SSRIs in first-episode drug-free patients with MDD.
Several limitations of the present study should be interpreted as follows: 1) A relatively small sample size. Our results should be considered a pilot study; 2) Comparison of IL-8 levels between patients with SSRIs and Healthy controls. Thus, it is unclear whether serum IL-8 levels are higher due to depression or the use of SSRIs; 3) A cross-sectional design. It was unclear whether there was a causative association between increased serum log10IL-8 levels and cognitive improvement in MDD patients with SSRIs. Thus, future longitudinal and prospective follow-up studies are necessary to clarify the relationships among serum log10IL-8 levels, cognition and SSRIs in first-episode drug-free patients with MDD; 4) Confirmed MDD diagnosis. Although patients were diagnosed as having unipolar depression rather than bipolar depression during enrollment, a few unipolar depressive patients may develop bipolar depression later; and 5) Types and dosages of SSRIs. Future studies should also examine the effect of different SSRI types and dosages on serum IL-8 levels and cognitive function in MDD patients.
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