Is serum complement C1q related to major depressive disorder?

BACKGROUND: Major depressive disorder (MDD) has a high global incidence. While the pathogenesis of depression remains unknown, accumulating evidence has implicated inflammatory changes. AIM: The aim of the study is to compare the serum complement C1q levels in patients with MDD and healthy controls. SETTING AND
DESIGN: The design was a case-control study.
MATERIALS AND METHODS: Blood samples were collected from the patients with MDD and healthy controls to assess the serum C1q levels using an immunotransmission turbidimetric method. STATISTICAL ANALYSIS: Differences in complement C1q levels between patients with MDD and the controls, as well as between sexes among patients with MDD and the controls, were assessed using Mann-Whitney U-test. Spearman correlations were obtained between complement C1q levels and age.
RESULTS: In total, 1016 participants (508 MDD and 508 controls) were recruited. Differences in the sex ratio (male/female among controls, 181/327; and MDD, 178/330) and age (controls, 47.0 ± 14.9 years; MDD, 46.5 ± 16.5 years) were not significant. The C1q level in the patients with MDD was significantly higher than that in the healthy controls (P < 0.05). In the MDD group, C1q level correlated significantly with age.
CONCLUSION: Elevation of the serum complement C1q levels in MDD may support the use of C1q as a potential biomarker for diagnosing depression, but further research is needed. Copyright:

INTRODUCTION

Major depressive disorder (MDD) is projected to account for the world's largest disease burden by 2030.[1] However, the pathogenesis of depression remains unclear. In recent years, increasing evidence has demonstrated that inflammation is associated with depression. Inflammation diminishes verbal memory and the speed of information processing and increases the negative attentional bias of patient of depression.[2] External stress may induce depression-like behavior through inflammation, oxidation, apoptosis, and activation of antineurogenic mechanisms.[3] The blood of the patients with MDD features an overall increase in the number of leukocytes.[4] Remission of depressive symptoms can lead to the improvement of lymphocyte response and natural killer cell activity.[5] These results collectively suggest that the pathogenesis of depression may be strongly related to inflammation.

The complement system mediates important immune responses between the innate and acquired immune systems, thus initiating various immune regulatory processes. Normally, the complement system undergoes a cascade of reactions, producing both complement and various immune substances that mediate many inflammatory responses. Therefore, abnormalities in the complement system can lead to abnormalities in the immune system.[6]

Complement C1q is involved in the classical complement pathway; thus, it is an important part of the natural immune system and vital for apoptotic cells, which activate the complement system and cause inflammation.[7] Throughout the gC1q region, C1q binds to immune complexes (immunoglobulin [Ig] G or IgM), which is believed to induce conformational changes in the collagen region of C1q.[8] In vivo, C1q binds to late apoptotic cells, activates the complement pathway, and enhances the phagocytosis of monocytes against apoptosis.[9] Everson-Rose et al.[10] reported an association between depressive symptoms and low adiponectin in middle-aged women with MDD, as the combination of adiponectin and C1q activated the classic complement system.[11] Therefore, C1q plays a role in complement activation, removal of immune complexes and necrotic cells, stimulation of cytokine production, regulation of lymphocyte function,[12] and emotional regulation.

Although there is convincing evidence that depression is strongly related to inflammation, changes in the serum C1q level of patients with MDD have not been reported. By comparing the C1q levels of the patients with MDD and healthy persons, this study explored whether there was an association between C1q and depression, with the hope of determining a potential biochemical basis for diagnosing MDD and providing a strong foundation for the immune inflammatory hypothesis of depression.

Aim of study

The primary aim of this study was to explore whether the difference in the C1q level was significant between patients of depression and healthy controls. The secondary aim was to assess whether the difference in the C1q level between depressed patients and healthy controls was related to age or sex.

MATERIALS AND METHODS

Subjects

This case–control study was conducted in the Department of Clinical Psychology of SuBei Hospital between January 2016 and June 2018. We enrolled 508 patients (178 men and 330 women) who met the following eligibility criteria: patients aged between 18 and 80 years; diagnosis of MDD according to the criteria specified in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (all enrolled subjects were evaluated by two professionally trained psychiatrists); patients with absence of any serious physical diseases, bipolar disorder with depressive episodes or other psychiatric diseases, and immune or endocrine system diseases; patients with no recent infections or vaccinations. The same number of healthy age- and sex-matched volunteers was enrolled as controls in accordance with the following exclusion criteria: patients with (1) history of MDD or other mental illness; (2) family history of any mental illness, immune system, or endocrine system disease; (3) recent infection or vaccination; (4) and serious physical disease.

This study was approved by the Ethics Committee of SuBei Hospital and performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants before they were enrolled.

Measurement of the serum C1q level

Samples of the venous blood were obtained on the day following hospitalization between 6:00 AM and 8:00 AM. Blood was drawn into coagulating tubes and left to clot for 1 h, followed by centrifugation for 4 min at 4000 rpm at room temperature. The separated serum samples were stored at −80°C until analysis. To measure the C1q level via the immunoturbidimetric test, we used a complement C1q assay kit according to the manufacturer's instructions. Briefly, the sample complement C1q antigen was specifically combined with rabbit antihuman complement C1q antiserum to form an insoluble immune complex. Turbidity was generated in the reaction solution. The concentration of complement C1q in the sample increased in direct proportion, and the absorbance increased accordingly. By comparison with the standard absorbance, the concentration of the complement C1q in the sample was calculated.

Statistical analyses

The baseline demographic characteristics between MDD group and healthy controls were compared by applying the Chi-square test for gender and Mann–Whitney U-test for age. As data of C1q levels were not normally distributed, nonparametric tests were used in this study. Differences in the complement C1q levels between patients with MDD and the controls, as well as between sexes among patients with MDD and the controls, were assessed using Mann–Whitney U-test. Spearman nonparametric correlations were obtained between complement C1q levels and age. All tests were two-tailed, with statistical significance defined as P < 0.05. Statistical analyses were performed using SPSS 16.0 for Windows (IBM Corp, Chicago, America).

RESULTS

The study sample comprised 1016 subjects (508 patients with MDD and 508 healthy controls). Data of age were not normally distributed, and the Mann–Whitney U-test was used to assess the difference between MDD and the controls. The difference of sex ratio between MDD and the controls was assessed with Chi-square test. There was no significant difference in the sex ratio and age distribution between the two groups. Details are provided in Table 1.

Table 1

Group characteristics

	Controls (n=508)	MDD group (n=508)	χ2/Z	P
Gender (male:female)	181:327	178:330	0.039	0.844a
Median age (P25-P75), years	50.0 (36.0-59.0)	47.0 (34.0-61.0)	0.611	0.541b

aChi-square test; bMann-Whitney U-test. P25-25th percentiles; P75-75th percentiles; MDD – Major depressive disorder

The results pertaining to primary aim

The median C1q level in the MDD group was 200.0 mgL−1 (25th percentile = 170.0 mgL−1, 75th percentile = 230.0 mgL−1). In the control group, the median value was 190.0 mgL−1 (25th percentile = 170.0 mgL−1, 75th percentile = 210.0 mgL−1). Thus, the C1q level was significantly higher in the MDD group than in the control group [Z = 5.005, P < 0.001; Figure 1a].

Figure 1

The C1q level is significantly higher in the depressive group than in the control (P = 0.022, a). The difference in the C1q level in depressive patients is significant between both sexes and healthy participants, as well as between depressive patients and the control, is significant in men and women (b). The correlation between the C1q level and age was analyzed (c) (r = 0.126, P = 0.0044, 95% confidence interval: 0.037–0.213)

The results pertaining to secondary aim

The C1q levels of the patients with MDD were divided into two groups according to sex. The median, 25th percentile, and 75th percentile of C1q levels in men were 190.0, 160.0, and 220.0 mgL−1 and in women were 220.0, 170.0, and 240.0 mgL−1, respectively. The C1q level was significantly higher in female patients with MDD than in the male patients with MDD (Z = 2.513, P = 0.012). In the control group, the median, 25th percentile, and 75th percentile of C1q levels in men were 186.0, 165.5, and 202.5 mgL−1 and in women were 188.0, 170.0, and 213.0 mgL−1, respectively. The difference between men and women was statistically significant (Z = 2.654, P = 0.008). Between the MDD group and control group, differences in the C1q level were statistically significant in men (Z = 2.498, P = 0.012) and women (Z = 4.183, P < 0.001). Those are shown in Figure 1b.

The relationship between C1q levels and age in the MDD group was assessed using the Spearman nonparametric correlation, and there was a significant positive correlation between age and serum C1q level [r = 0.126, P = 0.0044, 95% confidence interval: 0.037–0.213; Figure 1c].

DISCUSSION

Recent studies have indicated that C1q levels are significantly lower in patients with first-episode or drug-treated schizophrenia than in healthy controls.[13] Hyperactivity of C1q during pregnancy may be a risk factor for offspring with schizophrenia and mood disorders.[14] Depression is also a major mental disorder, and we speculate that C1q plays an important role in in mental disorders. Our study demonstrated an association between C1q and depression, but it is not yet confirmed whether this implicates C1q in the pathogenesis of depression; thus, further investigation of the underlying mechanisms is warranted. Although C1q levels are lower in patients with schizophrenia than in the healthy individuals,[13] the present study found that C1q levels were higher in patients with MDD than in healthy individuals; this discrepancy may be related to the different pathogenesis of these two diseases. Similarly, while glial fibrin and gene expression in astrocytes decrease in patients with depression, they increase in individuals with schizophrenia.[15] Both conditions, however, are associated with increases in active microglial markers.[1617] Astroglia regulate microglia,[18] and microglial cells are involved in neural immunity.[19] Thus, microglia and astrocytes require activation before they can repair neural circuits.[20] Although most evidence suggests that mental disorders, such as depression and schizophrenia, are related to neuroimmunity, few studies exist on the correlation between C1q and neuroimmunity in patients with mental disorders. Indeed, the role of neuroimmune cells, microglia, and astrocytes in mental disorders needs to be confirmed. C1q, as a component of immune pathways, may be associated with mental illness. So far, it is still unknown whether overactivity of the immune system is a cause or a product of depression. In other words, does an increase in the C1q level causes depressive symptoms, or does being depressed causes an increase in C1q levels? These two issues need to be investigated further. C1q and neural immunity need to be investigated in future studies.

Our study found that C1q levels increased with age in the MDD group, which was consistent with normal people.[21] Compared to men, women exhibit more obvious inflammatory responses.[22] In our study, women had higher C1q levels than did men. According to the World Health Organization, the prevalence of depression is greater among women than among men, and a high incidence of depression occurs between the ages of 55 and 74 years.[1] With increases in age, immune functions of the body decline.

This study is subject to several limitations: (1) the duration of overall illness as well as current episode of each patient's disease was not differentiated; (2) the severity of each patient's condition was not distinguished by the Hamilton Depression Rating Scale or any other rating scale score before the patient was enrolled; (3) patients with disease recurrence or aggravation did not undergo a corresponding cleaning period before blood sampling, so they could have been receiving psychotherapy and somatic treatments that may have confounded the research results; (4) we did not differentiate between patients admitted for psychological treatment from those admitted for physical treatment; and (5) some patients may have experienced psychotic symptoms and numerous episodes that might have confounded the results.

In summary, C1q levels in the patients with MDD were significantly different from those of the control group. Female patients among MDD as well as control group had higher level of C1q compared to males in respective groups. Thus, C1q may be used as a target to study the pathogenesis of patients of depression, and elevation of the serum C1q level in patients with MDD supports the use of C1q as a potential biomarker for diagnosing depression. However, since we still cannot determine the cause/effect relationship between depression and inflammation, further studies are needed.

Financial support and sponsorship

This study was supported by Foundation of Leading Personnel (Innovation Team) in Science and Education Health Project of Yangzhou (LJRC20184).

Conflicts of interest

There are no conflicts of interest.