The effects of gender and numbers of depressive episodes on serum S100B levels in patients with major depression

Kun Yang^{1, 2}, Guang-Rong Xie², Yi-Qiu Hu^{2, 3}, Fu-Qiang Mao¹ and Lin-Yan Su²

¹ Department of Psychiatry, Tianjin Medical University, 300070 Tianjin, People’s Republic of China.
² Mental Health Institute of the Second Xiangya Hospital, Central Southern University, No. 139 Renmin Middle Road, 410011 Changsha, People’s Republic of China.
³ Department of Students’ Job, Hunan University, 410082 Changsha, People’s Republic of China.

Abstract

S100B protein is a calcium-binding protein mostly derived from glial cells, which exerts trophic or toxic effects on neural cell depending on its concentration. It has been reported that S100B played an important role as a potential marker in psychiatric disorders. Thus, we will explore the clinical implication of S100B in major depression, especially the effect of gender and numbers of depressive episodes on S100B. The levels of serum S100B were measured with enzyme-linked immunosorbent assay (ELISA) in 54 patients with major depression and 35 age-matched healthy controls. The S100B levels in major depressed patients were significantly higher than those in controls. The serum S100B levels in female patients were significantly higher than those in male patients. Patients with recurrent depressive episodes had significantly higher S100B levels than those in first-episode depression. Serum S100B levels were significantly positive related with the numbers of depressive episode, family history and cognitive disturbance scores. These findings confirmed an increase in serum S100B levels in major depressive patients and presence of a sexual dimorphism. Moreover, numbers of depressive episodes in depression seemed to have an additional increasing effect on S100B levels.

Keywords: Major depression - Serum S100B - Gender - Numbers of depressive episode .

Table of contents

• Introduction
• Materials and methods
• Results
• Discussion
• References

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Introduction

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Depressive disorder is one of common and recurrent psychiatric diseases. Recently, researchers have reported the theory of neurotrophic mechanisms damaged in major depression (Duman et al. 2000). Therefore, it was thought that neurotrophic factors played an important role in the onset and treatment of depression. Neurotrophasthenia could cause neural plasticity damaged in the encephalic region such as hippocampus and amygdale (Shoval and Weizman 2005). Histological alterations in glial cells have been recently reported in mood disorders (Ongur et al. 1998; Rajkowska 2000; Cotter et al. 2001). Lara et al. (2001a, b) suggested that glial cells may not only contribute to the pathophysiology of mental disorders, but also deserve to be considered as targets for therapeutic intervention. Studies showed that neural plasticity in depression was related with the function of glial cells (Duman 2002).

Some studies have reported that S100B involved in the processes of neural plasticity. The S100B levels were increased in neurodegenerative diseases (Ostrovskaya et al. 2007). S100B were primarily produced and secreted by astrocytes in central nervous system (CNS) (Shashoua et al. 1984; Van Eldik et al. 1984). It was confirmed as an EF-hand calcium binding protein, and was similar with calmodulin and troponin in structure. In mammalians, S100B exists in astrocyte and oligodendrocyte in CNS and in the peripheral nervous system (Donato 1999), which modulates the proliferation and differentiation of neurons and glia (Rothermundt et al. 2004). In vivo studies with S100B knockout mice or over-expression of S100B in mice suggested that this protein was involved in cognitive functions such as spatial, non-spatial memory and learning (Nishiyama et al. 2002). Some evidences suggested that serotonin (5-HT) was involved in the regulation of S100B release via the 5-HT_1A receptor (Whitaker-Azmitia and Azmitia 1994). S100B was an astroglial-derived neurotrophic factor, and S100B level in serum or cerebrospinal fluid was a biological parameter of astrocyte dysfunction (Van Eldik and Wainwright 2003). S100B played a complicated neurotrophic role in 5-serotonin neurons, neurite growth and synaptogenesis (Eriksen and Druse 2001). It can be used to provide information on glial function to complement morphological studies, and it is a candidate marker of brain dysfunction in severe mental disorders (Arolt et al. 2002; Schroeter et al. 2002; Ongur et al. 1998; Rajkowska 2000; Cotter et al. 2001). Moreover, the researchers have demonstrated that antidepressant could cut down the concentration of S100B in depression with depressive symptoms improved. Therefore, these studies suggested that S100B could play an important role in major depressive disorder (Manev et al. 2001; Zhang 2007a).

There were few studies concerning the serum S100B levels in mood disorder (Arolt et al. 2002; Schroeter et al. 2002; Dietrich et al. 2004; Hetzel et al. 2005; Grabe et al. 2001; Rothermundt et al. 2001a, b). The results of their study were consistent that the S100B levels were increased in mood disorder. But their study samples included not only bipolar mood disorder, but also minor depression. In addition, a number of studies indicted that depressive disorder was a heterogeneity disease (Bockting et al. 2006; Paradis et al. 2006). Therefore, the different depression subgroups such as male/female and first-episode/recurrent depressive disorder deserve to be considered.

It is not well known whether S100B levels in Chinese major depressed patients were also always increased. Moreover, they have not performed any study about S100B levels in the subgroup suffering from major depression (gender: male and female; numbers of depressive episode: first-episode and recurrent depression). Therefore, the aim of the present study was to investigate S100B levels in major depressed patients and whether gender and numbers of depressive episodes have any effect on the levels of S100B.

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Materials and methods

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Subjects

A total of 89 subjects were chosen in the present study, and provided informed consent. Complete physical, neurological, and laboratory examinations were performed to show that all the subjects were free of significant physical or neurological illnesses, including any acute or chronic infectious, inflammatory, and immune disorders.

Fifty-four depressive disorder subjects (19 males, 35 females; mean age ± SD:33.98 ± 12.54 years; age range: 18-58 years) met DSM-IV (The Diagnostic and Statistical Manual of Mental Disorders, 4th edn) criteria for a principal diagnosis of unipolar major depression and had a 17-item Hamilton depression rating scale (HDRS) total score ≥21, all of them were outpatient of the clinic and inpatients of the Mental Health Institute of the Second Xiangya Hospital in Central Southern University. Diagnoses and evaluations of the HDRS and Hamilton anxiety rating scale (HARS) were carried out by two experienced research psychiatrists through semi-structured interviews in conjunction with all other available medical records. Patients who had been examined and given the same depression diagnoses by the two experienced psychiatrists were recruited into the study.

Patients with schizophrenia or other psychoses, organic mental disorders, substance dependence, obsessive-compulsive disorder, or any other primary psychiatric disorder were excluded. At the time of testing, all subjects were free of major psychotropic drugs for at least 4 weeks (free of Fluoxetine for at least 5 weeks). Low dose benzodiazepines were available for severe agitation and insomnia.

Thirty-five healthy subjects (14 males, 21 females; mean age ± SD: 36.29 ± 9.82 years; age range: 26-58 years) were recruited from the Medical Examination Center and Mental Health Institute of the Second Xiangya Hospital in Central Southern University in Changsha, all of them were reportedly healthy by the Medical Examination Center. In addition to the medical screening described here, they were also screened for personal and family (first-degree relative) history of mental disorders by a research psychiatrist using a semi-structured interview, they did not show to have any such disease. Moreover, HDRS total scores of these subjects, which were assessed by experienced psychiatrists, were all under seven.

Based on these data collected by clinical interviews and DSM-IV criteria for unipolar major depression, we counted the number of depressive episodes, established the onset age of the first depressive episode and classified two or more episodes of depression as recurrent-episode depression (n = 18).

Procedure

Investigations were carried out on the day after hospital admission. The severity of depressive symptoms was assessed according to the Chinese version of the HDRS. These patients were also evaluated with the Chinese version of the HARS (Zhang 1993).

Fasting venous blood (5 mL) was withdrawn from the ulnar vein with a sterile vacuum tube without additives between 7.00 and 7.30 h. Serum was separated after being placed for approximately 1 h, and then frozen at −70°C until analysis.

Determination of serum S100B level

S100B concentrations were determined by applying the enzyme-linked immunosorbent assay (ELISA), a quantitative measurement of human S100B in serum, according to the manufacturer’s instructions. This sandwich ELISA was based on combination of polyclonal antibody coated microtiter plate and HRP-labelled (HRP, horseradish peroxidase) monoclonal antibody conjugate. Three incubation steps were included (1st-standards, samples or controls, 2nd-conjugate, 3rd-substrate) separated by washing steps. Then optical density (OD) at 450 nm was read and standard curve was pictured. Serum S100B ELISA kit we used in the experiment was from Bionewtrans Pharmaciutical Biotechnology Co, Ltd (Lot number: QRCT-21001EIA\UTL). All assays were carried out by the same operator using the same instrument and the same recommended buffers, diluents, and substrates. For S100B, the inter- and intra-assay coefficients of variation were 5 and 6.5%, respectively. The serum S100B assays were carried out in the Laboratory Central of the Mental Health Institute in the Second Xiangya Hospital in Central Southern University in China.

Statistical analysis

SPSS for Windows 11.5 was used for analyzing the collected data. Data were generally reported as mean ± SD. The distributions of the all variables were checked by Kolmogorov-Smirnov test and all showed normal and equally or nearly to equally distribution. Student’s t test, and the χ² test were performed for the comparisons of some demographic data, the serum S100B levels between healthy controls and patients. Since a considerable effect of gender on the S100B levels was observed, the differences between the patients and the controls were separately investigated in women and men by one-way ANOVA, taking the S100B levels as dependent factor, the presence of disorder as fixed factor and the age and BMI as covariates. One-way ANOVA was carried out for the comparisons of the serum S100B levels in the first-episode, recurrent depression and healthy controls. Relationships between S100B and clinical variables were evaluated by using Pearson’s and Spearman’s correlation. A difference was considered significant at P < 0.05.

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Results

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Demographic data

The demographic data and main characteristics of the 89 study subjects were listed in Table 1. No significant difference was found in the male/female ratio between patients with depressive disorder and healthy controls (χ ² = 0.211; df = 1; P = 0.646) and no significant difference in body mass index (BMI) appeared between the groups (t = 0.184; df = 75.346; P = 0.855). There was also no significant difference in age between the major depressive disorder and healthy control groups (t = 0.919; df = 87; P = 0.361). This suggested that the general characteristics of two groups had satisfactory comparability (Table 1).

The comparison of serum S100B levels in depressive disorder patients and normal controls

Significant differences were found in S100B levels between the unipolar major depressed patients and the healthy controls (t = −2.352, df = 78.117, P = 0.021). Moreover, the S100B levels were higher in patients (1.44 ± 0.62 ng/mL) than those in controls (1.18 ± 0.27 ng/mL) (Table 2).

Gender difference in the serum levels of S100B between depressed patients and healthy controls

The comparison of S100B levels in the male (n = 19) and female (n = 35) patients and the male (n = 14) and female (n = 21) controls were analyzed using one-way ANOVA (P < 0.05). After multiple comparison, significant differences appeared in S100B levels between the male (1.27 ± 0.31 ng/mL) and female (1.47 ± 0.78 ng/mL) depressed patients (P = 0.033). However, no significant difference in S100B levels appeared between male (1.11 ± 0.21 ng/mL) and female (1.37 ± 0.52 ng/mL) controls (P > 0.05). There was no significant difference in S100B levels between male controls and male patients, between female controls and female patients (P > 0.05) (Table 2, Fig. 1).

The comparison of serum S100B levels in first-episode, recurrent depressive disorder and normal controls

The comparison of S100B levels in first-episode, recurrent depressive disorder and normal controls were analyzed using one-way ANOVA (P < 0.05). By multiple comparison, we found significant differences in S100B levels appeared between first-episode and recurrent depressive disorder (P < 0.05). There were significant differences in serum S100B levels between recurrent depressive disorder and controls (P < 0.01). However, no significant difference in S100B levels appeared between first-episode depression and controls (P > 0.05) (Table 3).

Correlation between S100B levels and clinical characters in depression

Significant correlations were found between S100B levels and numbers of depressive episodes (r = 0.258, P = 0.046), between S100B levels and family history in depression (r = 0.329, P = 0.008). But S100B levels were not related significantly with HAMD total scores in the depressed patients (r = 0.034, P = 0.403). We also found no significant correlation between S100B and present age, onset age, duration of illness in depression (Table 4).

The analysis of the relationship between S100B, and the factor scores in HAMD and HAMA in depressed patients

S100B level is correlated positively with cognitive disturbance factor scores in depressive disorder (P < 0.05) (Table 5). However, no significant correlation appeared between S100B levels and other HAMD, HAMA factor scores (P > 0.05).

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Discussion

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The main findings of our study were as follows: (1) depressed patients had significantly higher serum S100B levels than those of healthy controls, (2) female had significant higher S100B levels than male in major depressed patients, (3) the S100B levels were significantly higher in the recurrent depressed patients than those in the first-episode depressive subjects; (4) serum S100B levels were significant positive related with numbers of depressive episodes, with family history and cognitive disorder in depressed patients.

The serum S100B levels in depression

Despite the different scientific and methodological approaches such as the types of quantification assay leading to a variety of results, the majority of studies suggested that S100B may be relevant for the psychopathology of depressive illness. To ensure the reliability of measurement, we randomly chose two subjects on the other two locations in the 96-well microwell plate, and we found that the levels of S100B in the two replicated samples in the different locations were not different, which showed our measurements were reliable.

Our study found that the serum S100B levels in depressed patients were higher than those in controls, which was lined with the results reported by Schroeter, Dietrich, Hetzel, Grabe, Rothermundt and Arolt (Schroeter et al. 2002; Dietrich et al. 2004; Hetzel et al. 2005; Grabe et al. 2001; Rothermundt et al. 2001a, b; Arolt et al. 2003). This pilot study by Arolt et al. suggested that neuroprotective functions of S100B counterbalance neurodegenerative mechanisms that are involved in the pathophysiology of major depression and in the response to antidepressant treatment. In a study of 20 patients with mood disorder and 12 age-matched healthy subjects, Schroeter et al. found that the severity degree of depressive symptoms was positively correlated with the S100B concentrations. But our study failed to find the relation between S100B and severity of depressive symptoms upon admission, we presumed it was possible because of different samples: the subjects we selected were major depressed patients and their study included bipolar disorders. The increases in serum S100B concentrations were suggested S100B was an important marker in destroyed neurons. It might increase the concentration of superoxide, decrease the capability that superoxide acquired free radicals, and raise the vulnerability that the cells were impaired by a free radical (Zhang 2007a). As far as S100B is concerned as a marker for damaged astrocytes, the increase in serum S100B levels possibly incriminated the destroyed astrocytes and the impaired blood-brain barrier, also may be due to the increases of S100B excreted by astrocytes (Zhang 2007b).

Recently, it has been reported that there was the relationship between S100B levels and the attention process in remitted depressive patients (Dietrich et al. 2004). It was confirmed further that S100B was interpreted as a potential marker indicating repair or remodeling processes for dysfunctional neurons and astrocytes in major depression (Hetzel et al. 2005).

Previous studies have showed that the serum S100B levels were increased in schizophrenia (Rothermundt et al. 2001a, b, 2004; Ongur et al. 1998; Grabe et al. 2001; Lara and Souza 2000), similar with our findings that the S100B levels were increased in major depression. In addition, a recent study showed that the serum or plasma S100B concentrations were heightened in stress disorders (Scaccianoce et al. 2004). But it also was found that serum S100B levels were decreased in schizophrenia (Gattaz et al. 2000) and mania disorders (Machado-Vieira et al. 2002). Therefore, we were not able to regard serum S100B levels as a specific maker in major depression.

The effect of gender on serum S100B levels

It was found there were significant differences in the levels of S100B between male and female depressed patients in this study. Moreover, the S100B levels in female depressed patients were higher than those in healthy controls. This elucidated that gender differences did exist in the S100B levels in major depression. The reasons which we explained the gender differences may be the differences in coping style for receiving stimulates, endocrine secretion, society role, and in cognition modes. As we know, the number of female suffering from depression in one’s life is as twice as likely as male’s. Furthermore, the gender differences primarily emerged at puberty and declined after menopause, highlighting the complex and reciprocal interactions that occur between biological, psychological and socio-cultural factors (Mazure et al. 2002). Futhermore, Nygaard et al. (1997) found sex-related dependency of S-100 protein in CSF, with significantly higher concentrations in men than in women. Hetzel et al. (2005) did not consider the effect of gender on serum S100B in depression; Arolt et al. (2002) did not find gender differences. We guessed the reason for the discrepancy may be the different samples. It is needed to study the effects of gender on S100B levels in a larger sample of MDD in the future.

The effect of episode numbers on serum S100B

Long-time follow-up investigation for depression found that depressive disorder was easy to recur. Angst et al. showed 10-20% patients were under the recurrent depressive disorder in 25 years follow-up study (Angst and Hochstrasser 1994, 1997). There was no study investigating the effects of numbers of depressive episodes on S100B levels in psychiatric diseases. This study found there were different S100B levels in different depressive episode numbers: the S100B levels in first-episode depression were significantly lower than those in recurrent depression; the S100B levels in recurrent depression were significantly higher than those in healthy controls. These findings suggested that numbers of depressive episodes influence serum S100B in major depression. Moreover, correlation analysis showed the serum S100B levels were positively correlated with the numbers of depressive episodes. This better confirmed that episode numbers effect on S100B in depression. However, other studies concerning S100B levels in depression did not deal with the effect of episode numbers (subtype) on S100B. This reason still has remained uncertain at the present.

S100B and clinical characters of MDD

Our study showed the serum S100B levels were positively correlated with family history (P < 0.05). But whether family history influence the serum S100B level is under current study. We have performed the association between the polymorphisms of rs11911834 and rs9722 in S100B gene and MDD, and found that although the two SNPs of S100B were not associated with MDD, there were significant differences in the three genotypes between first episode and recurrent depression (Yang et al. 2008). This supported that S100B might be related the family history in MDD.

This study showed a significant correlation relationship appeared between serum S100B and cognitive disturbance in HDRS, and it was well known to us that cognitive dysfunction was an important clinical presentation in depression. This manifested S100B possibly involved in the pathology of depression. It was thought that S100B was one of potential nutrition factor in 5-HT neurons in CNS (Eriksen and Druse 2001). In fact, in vitro studies made it clear that the outstanding reduction or depletion of S100B levels impaired the development of 5-HT, also influenced the development of astrocyte (Druse et al. 2007; Tajuddin et al. 2003; Eriksen et al. 2002; Nishiyama et al. 2002). Many studies on the pharmacological mechanisms of antidepressant manifested 5-HT dysfunction appeared in MDD (Izumi et al. 2007; Meyer 2007). These studies showed that S100B played an important role in depression, but the mechanism of it in major depression yet have not been understood.

In conclusion, our study showed that S100B played an important role in major depression. S100B levels in depression were significantly higher than those in controls, and different S100B levels appeared in first-episode and recurrent depression, and serum S100B presented gender dimorphism. But at present this mechanism cannot be understood, it was necessary to further augment samples and perform the animal studies and clinical studies about S100B levels in major depression.

Acknowledgments  The authors are grateful to Dr. Jie Li (Department of Psychiatry, Tianjin Medical University) for helpful revising the manuscript. The authors thanked all doctors and nurses who participated in our study in the Second Xiangya Hospital of Central Southern University for technical assistance. Moreover, we appreciated all patients and normal controls in our study.

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Journal of Neural Transmission 2008; aop: 10.1007/s00702-008-0130-8