Introduction
Major depressive disorder (MDD) has become a common and severe psychiatric disorder, typically characterized by one or more episodes of depressive mood, markedly diminished interest or pleasure, and even recurrent thoughts of death. The prevalence of MDD is approximately 17% in a Chinese population (Philips et al. Reference Philips, Zhang, Shi, Song, Ding and Pang2009). Although MDD mainly involves the disturbance of mood, attention impairment has been identified as one of its core features (McDermott & Ebmeier, Reference McDermott and Ebmeier2009; Lee et al. Reference Lee, Hermens, Porter and Redoblado-Hodge2012). The capacity of attention supports the key cognitive processes and reports cognitive problems such as lack of effort, memory deficit, and slowed information processing, which might be secondary to attention impairment (Lezak, Reference Lezak1982; Mesulam, Reference Mesulam1985; Williams et al. Reference Williams, Hagerty, Cimprich, Therrien, Bay and Oe2000). Previous studies have indicated that the capacity of attention was significantly impaired in patients with MDD (Kemp et al. Reference Kemp, Hopkinson, Hermens, Rowe, Sumich and Clark2009; Cotrena et al. Reference Cotrena, Branco, Shansis and Fonseca2016). Our recent finding also showed that the score of the attention index in patients with MDD was significantly lower than that in healthy controls (Shao et al. Reference Shao, Yin, Yin, Wu, Du and Zhu2017). Moreover, the impairment of sustained attention has been regarded as a potential marker of MDD (Rock et al. Reference Rock, Roiser, Riedel and Blackwell2014), which has been investigated in different subgroups of MDD. For example, a study showed that sustained attention in adolescents with MDD in the acute episode was impaired compared with healthy controls (Maalouf et al. Reference Maalouf, Brent, Clark, Tavitian, McHugh and Sahakian2011). There was a significant difference in sustained attention between unmediated patients with current MDD and healthy controls (Porter et al. Reference Porter, Gallagher, Thompson and Young2003; van der Meere et al. Reference van der Meere, Börger and van Os2007; Braw et al. Reference Braw, Aviram, Bloch and Levkovitz2011; Yang et al. Reference Yang, Ma, Huang, Sun, Zhao and Lin2015). Remitted patients with MDD were also found to exhibit a greater impairment of sustained attention than healthy controls (Paradiso et al. Reference Paradiso, Lamberty, Garvey and Robinson1997; Paelecke-Habermann et al. Reference Paelecke-Habermann, Pohl and Leplow2005; Maalouf et al. Reference Maalouf, Brent, Clark, Tavitian, McHugh and Sahakian2011). Taken together, these studies support the notion that the impairment of sustained attention in patients with MDD may be considered a potential target for clinical and psychosocial treatments. However, the pathophysiology of sustained attention impairment in patients with MDD remains unclear and requires further investigation.
The pathogenesis of MDD may be involved in the initiation of neuroinflammation, which is associated with several pathophysiological processes, such as activation of the hypothalamic-pituitary-adrenal axis, depletion of tryptophan for serotonin conversion, and decreased neuroplasticity (Danese et al. Reference Danese, Moffitt, Pariante, Ambler, Poulton and Caspi2008; Miller et al. Reference Miller, Maletic and Raison2009; Felger & Lotrich, Reference Felger and Lotrich2013). The immune developmental hypothesis for MDD has been supported by several lines of evidence including increased serum levels of inflammatory markers (Liu et al. Reference Liu, Ho and Mak2012; Howren et al. Reference Howren, Lamkin and Suls2009; Dowlati et al. Reference Dowlati, Herrmann, Swardfager, Liu, Sham and Reim2010), emergence of depressive symptoms following inflammation-based treatments (Capuron et al. Reference Capuron, Gumnick, Musselman, Lawson, Reemsnyder and Nemeroff2002; Dantzer et al. Reference Dantzer, O'Connor, Freund, Johnson and Kelly2008; Raison et al. Reference Raison, Rutherford, Woolwine, Shuo, Schettler and Drake2013), and the link between inflammatory activation and abnormal functions in the prefrontal cortex of MDD patients (Setiawan et al. Reference Setiawan, Wilson, Mizrahi, Rusjan, Miler and Rajkowska2015). Recently, genetic studies have further highlighted the role of the immune system by detecting the susceptible genes and chromosomal regions as the risk loci of MDD (Anders et al. Reference Anders, Tanaka and Kinney2013; Goodyer, Reference Goodyer2015).
Interleukin 6 (IL-6) is a multifunctional cytokine that regulates the growth and differentiation of various cells and plays a critical role in immune response and acute phase reactions (Kopf et al. Reference Kopf, Baumann, Freer, Freudenberg, Lamers and Kishimoto1994; Kiecolt-Glaser et al. Reference Kiecolt-Glaser, Preacher, MacCallum, Atkinson, Malarkey and Glaser2003). In addition, at the molecular level, the il-6 gene on human chromosome 7p15 was identified as a risk gene for MDD (Camp et al. Reference Camp, Lowry, Richards, Plenk, Carter and Hensel2005). The mutations of the il-6 gene were also involved in susceptibility to MDD (Udina et al. Reference Udina, Moreno-España, Navinés, Giménez, Langohr and Gratacòs2013; Tartter et al. Reference Tartter, Hammen, Bower, Brennan and Cole2015; Zhang et al. Reference Zhang, Wu, Zhao, Wang and Fang2016). Thus, it is possible that the increasing expression of the il-6 gene was associated with the etiology of MDD (Yi et al. Reference Yi, Li, Yu, Yuan, Hong and Wang2012; Jansen et al. Reference Jansen, Penninx, Madar, Xia, Milaneschi and Hottenga2016; Zhang et al. Reference Zhang, Wu, Zhao, Wang and Fang2016).
Conversely, at the protein level, serum IL-6 contents were also significantly higher in patients with MDD than in healthy controls (Liu et al. Reference Liu, Ho and Mak2012; Howren et al. Reference Howren, Lamkin and Suls2009; Dowlati et al. Reference Dowlati, Herrmann, Swardfager, Liu, Sham and Reim2010; Goldsmith et al. Reference Goldsmith, Rapaport and Miller2016). Similarly, IL-6 levels were also found to be significantly higher in the CSF of patients with MDD compared with healthy controls (Kern et al. Reference Kern, Skoog, Bőrjesson-Hanson, Blennow, Zetterberg and Ostling2014). However, after treatment with antidepressants, IL-6 levels were significantly reduced in patients with MDD (Hiles et al. Reference Hiles, Baker, de Malmanche and Attia2012; Dahl et al. Reference Dahl, Ormstad, Aass, Malt, Bendz and Sandvik2014; Yang et al. Reference Yang, Ma, Huang, Sun, Zhao and Lin2015). Collectively, serum IL-6 may be considered a potential biomarker for MDD.
Previous studies have shown that elevated IL-6 levels may influence cognitive functions. For example, there is an inverse relationship between plasma IL-6 levels and cognitive functions in patients with MDD (Marioni et al. Reference Marioni, Strachan, Reynolds, Lowe, Mitchell and Fowkes2010; Grassi-Oliveira et al. Reference Grassi-Oliveira, Bauer, Pezzi, Teixeira and Brietzke2011; Goldsmith et al. Reference Goldsmith, Rapaport and Miller2016). Plasma IL-6 levels were reported to be negatively correlated with semantic fluency, auditory recognition memory, working memory, and executive function in healthy adults (Marsland et al. Reference Marsland, Petersen, Sathanoori, Muldoon, Neumann and Ryan2006; Wright et al. Reference Wright, Sacco, Rundek, Delman, Rabbani and Elkind2006; Gimeno et al. Reference Gimeno, Marmot and Singh-Manoux2008). Positive associations between IL-6 levels and cognitive deficits derived from a number of cognitive domains have been reported in older subjects (Jordanova et al. Reference Jordanova, Stewart, Davies, Sherwood and Prince2007; Gimeno et al. Reference Gimeno, Kivimäki, Brunner, Elovainio, De Vogli and Steptoe2009; van den Kommer et al. Reference van den Kommer, Dik, Comijs, Jonker and Deeg2010; Lekander et al. Reference Lekander, von Essen, Schultzberg, Andreasson, Garlind and Hansson2011; Mooijaart et al. Reference Mooijaart, Sattar, Trompet, Lucke, Stott and Ford2013; Simpson et al. Reference Simpson, Hodkinson, Maylor, McCormack, Rae and Strain2013; Heringa et al. Reference Heringa, van den Berg, Reijmer, Nijpels, Stehouwer and Schalkwijk2014). Increased IL-6 levels may predict worse cognitive performance in elderly patients with type 2 diabetes (Rafnsson et al. Reference Rafnsson, Deary, Smith, Whiteman, Rumley and Lowe2007). Moreover, several studies have shown that higher IL-6 levels were significantly associated with the impairment of attention function in patients with other psychiatric disorders (Frydecka et al. Reference Frydecka, Misiak, Pawlak-Adamska, Karabon, Tomkiewicz and Sedlaczek2015). However, to our best knowledge, no studies have examined serum IL-6 levels in relation to sustained attention in patients with MDD. Therefore, the aim of the present study was to examine whether altered IL-6 levels are associated with the impairment of sustained attention in patients with MDD.
Methods
Ethics statement
This study was conducted between August 2016 and May 2017. Following a complete description of the study protocol and procedures to each individual by a psychiatrist or research coordinator, written informed consent was obtained in accordance with the study protocol that was approved by the Institutional Review Board at the Affiliated Guangji Hospital of Soochow University.
Subjects
Patients with MDD (n = 30; male/female = 12/18) were recruited from inpatient unit of the Affiliated Guangji Hospital of Soochow University, a Suzhou City owned psychiatric hospital. The catchment area of this hospital covered a population of approximately 10.6 million individuals. All MDD patients met the following inclusion criteria: (1) aged 18–60 years old, Han Chinese; (2) confirmation of unipolar depression by two psychiatrists using the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV); (3) had a minimum of 6 years of education; (4) had received treatment with oral antidepressants; and (5) had the ability to participate in cognitive assessment. In addition, all patients received a balanced diet during a hospital stay.
For the initial screening, we applied the DSM-IV to define cases of depression. The PHQ-9 evaluates the reliability and validity of Public Health Questionnaires. A recent study (Wang et al. Reference Wang, Bian, Zhao, Li, Wang and Du2014) has indicated that the Chinese version of the PHQ-9 is a valid and efficient tool with a sensitivity of 0.86 and a specificity of 0.86 for screening depression. Therefore, we subsequently used the PHQ-9 (⩾7) to further confirm the diagnosis.
Healthy controls (n = 30; male/female = 13/17) were recruited from the local community in the Gusu District of Suzhou. All enrolled subjects met the following criteria: (1) aged 18–60 years, Han Chinese; (2) received education for at least 6 years; (3) had the ability to participate in cognitive assessment; and (4) had a PHQ-9 total score <7. Current mental status and personal or family history of any mental disorder were assessed using unstructured interviews. None of the healthy controls had MDD. All subjects were in good physical health. Any subjects with schizoaffective disorders, dementia, neurodegenerative and neurological disorders, cardiovascular disease, cerebrovascular disease, infections, cancer, diabetes, hypertension, hyperlipidemia, or pregnant were excluded. Neither patients with MDD nor healthy controls had drug or alcohol abuse/dependence.
Clinical measures
A detailed questionnaire including a complete medical history, physical examination, and medical and psychological conditions was obtained from each subject. Additional information including age, gender, education, smoking, and duration of illness was collected from available medical records.
The capacity of sustained attention was assessed using the Chinese version of Rapid Visual Information Processing (RVP) task in the Cambridge Neuropsychological Tests Automated Battery (CANTAB). The RVP was useful to evaluate the dysfunctions in the parietal and frontal lobe areas of the brain in patients with MDD and was also a sensitive measure of general focusing performance. Several previous studies have shown that RVP was a valid clinical measure to assess sustained attention in healthy populations and patients with neuropsychiatric disorders (Sahakian & Owen, Reference Sahakian and Owen1992; Mann, et al. Reference Mann, Williams, Ward and Janelle2007). For the RVP task, a white box appeared in the center of the computer screen and inside the box digits (ranging from 2 to 9) appeared in a pseudo-random order at a rate of 100 digits/min. Each subject was required to focus on the screen continuously to detect the target sequences of three digits (2-4-6, 3-5-7, and 4-6-8) and subsequently, to register their responses using a touch pad. A total of three indices of RVP were recorded: (1) total hits (the subject responding correctly to the target sequence; the higher the score, the better); (2) total misses (the subject failed to respond to a target sequence; the lower the score, the better); and (3) mean latency (mean time taken to respond to correct responses in milliseconds).
Moreover, other cognitive functions (online Supplementary Table S1) were assessed using motor screening, delayed matching to sample, big little circle, and intra-extra dimensional in the CANTAB in each subject.
IL-6 measurement
Blood samples without anticoagulants were collected from the MDD patients and healthy controls between 7 and 9 AM following an overnight fasting. The serum was separated, aliquoted, and stored at −80 °C in a refrigerator before laboratory assays. Freedom EVOlyzer (Tecan, Sweden) was used to measure the serum IL-6 levels using a commercially available sandwich enzyme-linked immunosorbent assays kit (Boster, Wuhan, China). A detailed procedure has been published elsewhere (Kouwenhoven, et al. Reference Kouwenhoven, Ozenci, Teleshova, Hussein, Huang and Eusebio2001; Góra-Gebka, et al. Reference Góra-Gebka, Liberek, Szydlowska-Lysiak, Bako and Korzon2003). The sensitivity was 0.3 pg/ml, with intra-assay variation coefficients of 5%, and inter-assay variation coefficients of 7%. A standard curve was established in triplicate for each plate. The assays were performed by the same technician who was blind to the sample's ID and clinical information.
Statistical analysis
Demographic and clinical variables were compared between patients with MDD and healthy controls using an analysis of variance (ANOVA) for continuous variables and a c2 test for categorical variables. The RVP scores and serum IL-6 levels were not normally distributed and were thus log-transformed. We then compared log10 RVP scores and log10IL-6 levels between two groups using an ANOVA. When significance was found in the ANOVA, the potential confounding factors were added as covariates. The relationships between log10IL-6 levels and log10RVP scores in patients with MDD and healthy controls were evaluated with Pearson's product moment correction coefficients. A multivariate regression analysis using the stepwise method was used to identify the potential variables that affected log10RVP scores. SPSS version 17.0 was used to perform all statistical analyses. In addition, correction analysis further investigated the associations between log10IL-6 levels and other cognitive functions in patients with MDD and healthy controls. Continuous data were presented as the mean and standard deviation (mean ± s.d.), and all p values were 2-tailed at a significance level of <0.05.
Results
Demographic and clinical characteristics
There were no significant differences in gender, age, education, smoking, and body mass index (BMI) between patients with MDD and healthy controls (Table 1). The mean and s.d. of heart rate, systolic and diastolic pressures, and illness duration (years) in patients with MDD were 78.87 ± 7.04, 121.70 ± 10.93, 76.97 ± 6.76, and 69.95 ± 85.62, respectively. The types of antidepressants included single selective serotonergic reuptake inhibitor (SSRI, n = 14, 46.67%), other single antidepressants (n = 7, 23.33%), and combined antidepressants (n = 9, 30.00%).
Table 1. Demographic and clinical variables in patients with MDD and healthy controls
Mean ± s.d. (standard deviation); BMI, body mass index; SSRI, selective serotonergic reuptake inhibitor.
Comparisons of RVP scores and serum IL-6 levels between MDD patients and healthy controls
The mean and s.d. of log10RVP scores in 30 patients with MDD and 30 healthy controls are shown in Table 2. There were significant differences in log10RVP total hits (1.21 ± 0.12 v. 1.28 ± 0.12, F = 6.04, p = 0.017), log10RVP total misses (0.95 ± 0.22 v. 0.67 ± 0.26, F = 19.77, p < 0.0001), and log10RVP mean latency (2.66 ± 0.13 v. 2.55 ± 0.10, F = 14.42, p < 0.0001) between the two groups. Moreover, log10IL-6 levels were significantly higher in patients with MDD than in healthy controls (Fig. 1, 1.05 ± 0.17 v. 0.45 ± 0.16, F = 192.27, df = 58, p < 0.0001).
Fig. 1. Comparisons of serum log10IL-6 levels between patients with MDD and healthy controls. Serum log10IL-6 levels were significantly higher in patients with MDD than in healthy controls (1.05 ± 0.17 v. 0.45 ± 0.16, F = 192.27, df = 58, p < 0.0001). MDD, major depressive disorder; HC, healthy controls.
Table 2. Comparisons of log10RVP scores between patients with MDD and healthy controls
RVP, Rapid Visual Information Processing; MDD, major depressive disorder.
Significant p values (<0.05) are highlighted in boldface.
Associations between RVP scores and serum IL-6 levels
In patients with MDD, the Pearson correlation analysis showed a significantly positive correlation between log10IL-6 levels and log10RVP mean latency in Fig. 2a (r = 0.45, df = 1, 28, p = 0.013). However, such a correlation was not found in healthy controls (Fig. 2b, r = 0.04, df = 1, 28, p = 0.82). A further stepwise multivariate regression analysis showed that log10IL-6 levels were significantly associated with log10RVP mean latency in MDD patients (β = 0.31, t = 2.41, p = 0.025). By contrast, log10IL-6 levels were not associated significantly (p > 0.05) with other cognitive functions, i.e. log10RVP total hits and log10RVP total miss in MDD patients. There were also no associations between log10IL-6 levels (or log10RVP scores) and antidepressant treatment. The correlation coefficient data between log10IL-6 and other cognitive function measures were detailed in online Supplementary Table S1.
Fig. 2. Correlations between serum log10IL-6 levels and log10RVP mean latency in patients with MDD (a) and healthy controls (b). A significant correlation was found in MDD patients (r = 0.45, n = 30, p = 0.013), but not in healthy controls (r = 0.04, n = 30, p = 0.82).
In healthy controls, there were also no correlations between log10IL-6 levels and log10RVP scores. In addition, log10IL-6 levels were not correlated with other cognitive functions.
Discussion
In accordance with our recent data evaluating cognitive functions in MDD patients using the Repeatable Battery for the Assessment of Neuropsychological Status (Shao et al. Reference Shao, Yin, Yin, Wu, Du and Zhu2017), the present study also demonstrated a higher degree of sustained attention deficits in MDD patients than in healthy controls. Increasing evidence has shown that the deficits of sustained attention appear in different stages of MDD development (Paradiso et al. Reference Paradiso, Lamberty, Garvey and Robinson1997; Porter et al. Reference Porter, Gallagher, Thompson and Young2003; Paelecke-Habermann et al. Reference Paelecke-Habermann, Pohl and Leplow2005; van der Meere et al. Reference van der Meere, Börger and van Os2007; Braw et al. Reference Braw, Aviram, Bloch and Levkovitz2011; Maalouf et al. Reference Maalouf, Brent, Clark, Tavitian, McHugh and Sahakian2011). Collectively, attention deficits may be considered a core feature of MDD (McDermott & Ebmeier, Reference McDermott and Ebmeier2009; Lee et al. Reference Lee, Hermens, Porter and Redoblado-Hodge2012).
Moreover, there was a significant association between attention deficits and brain structural dysfunctions. Specifically, the changes of gray matter volume in the inferior frontal gyrus were significantly correlated with sustained attention in patients with MDD (Yang et al. Reference Yang, Ma, Huang, Sun, Zhao and Lin2015). The abnormal prefrontal cortex was also significantly associated with attention deficits in remitting and non-remitting recurrent depression patients (Li et al. Reference Li, Lin, Chou, Chen, Hsieh and Wu2010). It is possible that brain abnormalities in the lingual gyrus and frontoparietal network may play a critical role in the regulation of sustained attention (Coull et al. Reference Coull, Frith, Frackowiak and Grasby1996; Jung et al. Reference Jung, Kang, Won, Nam, Lee and Tae2014). Future investigations in neuroimaging-attention are necessary in a large and independent cohort of MDD patients.
In the brain, IL-6 acts as a neurotrophic factor expressed in both neurons and glia (Loddick et al. Reference Loddick, Turnbull and Rothwell1998). Increased levels of IL-6 have been consistently demonstrated in the plasma (Liu et al. Reference Liu, Ho and Mak2012; Howren et al. Reference Howren, Lamkin and Suls2009; Dowlati et al. Reference Dowlati, Herrmann, Swardfager, Liu, Sham and Reim2010; Goldsmith et al. Reference Goldsmith, Rapaport and Miller2016) and CSF (Kern et al. Reference Kern, Skoog, Bőrjesson-Hanson, Blennow, Zetterberg and Ostling2014) of MDD patients. Moreover, a recent longitudinal cohort study showed that higher IL-6 levels in childhood were significantly associated with subsequent persistent depressive symptoms (Khandaker et al. Reference Khandaker, Stochl, Zammit, Goodyer, Lewis and Jones2017). However, IL-6 levels may be regulated by the presence of antidepressants (Hiles et al. Reference Hiles, Baker, de Malmanche and Attia2012; Dahl et al. Reference Dahl, Ormstad, Aass, Malt, Bendz and Sandvik2014; Yang et al. Reference Yang, Ma, Huang, Sun, Zhao and Lin2015). By contrast, several prospective studies have argued against an altered level of IL-6 in MDD patients (van den Biggelaar et al. Reference van den Biggelaar, Gussekloo, de Craen, Frölich, Stek and van der Mast2007; Milaneschi et al. Reference Milaneschi, Corsi, Penninx, Bandinelli, Guralnik and Ferrucci2009; Stewart et al. Reference Stewart, Rand, Muldoon and Kamarck2009; Chocano-Bedoya et al. Reference Chocano-Bedoya, Mirzaei, O'Reilly, Lucas, Okereke and Hu2014). Such inconsistent findings may be due to several confounding factors including BMI, smoking, antidepressants, sleep, and cognitive dysfunctions (Duivis et al. Reference Duivis, de Jonge, Penninx, Na, Cohen and Whooley2011).
It is not clear whether peripheral changes of IL-6 are directly related to the structural and functional changes of the brain. In the present study, serum IL-6 levels were negatively correlated with sustained attention in patients with MDD in a Chinese population. It is surmised that sustained attention may be mediated through afferent nerves resulting from increased levels of serum IL-6 (Capuron & Miller, Reference Capuron and Miller2011). Recent studies have further shown that IL-6 levels are negatively related to cognitive functions in patients with MDD (Marioni et al. Reference Marioni, Strachan, Reynolds, Lowe, Mitchell and Fowkes2010; Grassi-Oliveira et al. Reference Grassi-Oliveira, Bauer, Pezzi, Teixeira and Brietzke2011; Goldsmith et al. Reference Goldsmith, Rapaport and Miller2016). Similarly, elevated IL-6 levels were also involved in attention impairment in patients with other mental disorders (Marsland et al. Reference Marsland, Petersen, Sathanoori, Muldoon, Neumann and Ryan2006; Frydecka et al. Reference Frydecka, Misiak, Pawlak-Adamska, Karabon, Tomkiewicz and Sedlaczek2015) and in cognitive dysfunctions in the elderly with (Rafnsson et al. Reference Rafnsson, Deary, Smith, Whiteman, Rumley and Lowe2007) and without (Gimeno et al. Reference Gimeno, Kivimäki, Brunner, Elovainio, De Vogli and Steptoe2009; Heringa et al. Reference Heringa, van den Berg, Reijmer, Nijpels, Stehouwer and Schalkwijk2014) type 2 diabetes. However, further studies investigating the relationships between other cytokines and sustained attention, and their environmental interactions are warranted in patients with MDD.
There are several limitations in the present study: (1) A relatively small sample size. Our findings should be considered a pilot study. (2) Employing banked samples that were collected from August 2016 to May 2017, and were stored at −80 °C in a refrigerator for differing lengths of time. Although the storage time may influence the laboratory IL-6 assay, the normal range of serum IL-6 (1.44–5.25 pg/ml) in the present study was very comparable to a previously published range of 1–8.14 pg/ml (Ganguli et al. Reference Ganguli, Yang, Shurin, Chengappa, Brar and Gubbi1994; Akiyama, Reference Akiyama1999; Borovcanin et al. Reference Borovcanin, Jovanovic, Radosavljevic, Djukic Dejanovic, Bankovic and Arsenijevic2012; Di Nicola et al. Reference Di Nicola, Cattaneo, Hepgul, Di Forti, Aitchison and Janiri2012; Upthegrove et al. Reference Upthegrove, Manzanares-Teson and Barnes2014; Noto et al. Reference Noto, Maes, Ota, Teixeira, Bressan and Gadelha2015). (3) A cross-sectional research design. Future studies with longitudinal and prospective follow-ups are necessary to clarify the association between serum IL-6 levels and sustained attention in patients with MDD. It is thus not clear whether there is a causative relationship between elevated IL-6 levels and sustained attention deficits in MDD patients. (4) Limited sample volume. The present study was only able to focus on serum IL-6 that had direct implications on the pathophysiology of MDD. Thus, future studies shifting the focus from individual cytokines including CRP to networked activation of cytokines are warranted. (5) Confirmed diagnosis of MDD. Although the patients were confirmed with a diagnosis for unipolar depression rather than bipolar depression at the entry level of the study, a few unipolar depressive patients may develop to bipolar depressive patients in the follow-ups. (6) Effect of antidepressants. As indicated in the Introduction, IL-6 levels were found significantly reduced in patients with MDD after treatment with antidepressants (Hiles et al. Reference Hiles, Baker, de Malmanche and Attia2012; Dahl et al. Reference Dahl, Ormstad, Aass, Malt, Bendz and Sandvik2014; Yang et al. Reference Yang, Ma, Huang, Sun, Zhao and Lin2015). In accordance with previously published data, the present finding also demonstrated significantly higher levels of serum IL-6 in MDD patients than in healthy controls. Thus, our MDD patients may have even higher levels of IL-6 if they were not treated with antidepressants. Finally, (7) the absence of other clinical assessments including illness duration, and sleep status. Future studies should be expanded to include those clinical assessments having effects on serum IL-6 levels and sustained attention in MDD patients.
In summary, the serum IL-6 levels were higher and impairment of sustained attention was greater in patients with MDD than in healthy controls. The serum IL-6 levels were positively associated with the RVP mean latency in patients with MDD. Our data further demonstrated that abnormal levels of serum IL-6 may reflect an imbalance between pro- and anti-inflammatory mechanisms underlying the psychopathology of MDD. Furthermore, IL-6 may play a vital role in the impairment of sustained attention in patients with MDD. However, the present findings were only preliminary due to the relatively small sample size and absence of a longitude follow-up. Therefore, future investigations are warranted to confirm the present findings in a large and independent cohort of MDD patients.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/S0033291718000090
Acknowledgements
This study was funded by the grants from National Natural Science Foundation of China (81771439 and 81501160), Young Medical Talent of Jiangsu Province (QNRC2016228), Suzhou Key Medical Center for Psychiatric Diseases (Szzx201509), Suzhou Key Laboratory for Biological Psychiatry (SZS201722), Wenzhou Municipal Sci-Tech Bureau Program (Y20170077 and Y20160073), and Zhejiang Province Rising Star in Medicine. These sources had no further role in the design of this study, data collection and analysis, writing of the report, and decision to submit the paper for publication.
Declaration of Interest
The authors declare no conflict of interest.
