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Keywords:

  • cytokine;
  • IL-10;
  • IL-1β;
  • major depression;
  • TNF-α

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Abstract  Several studies have discussed the relationships between T-helper 1 (Th1) or Th2 cytokines and major depression. The aim of the present study was to investigate the relationships between Th1/Th2 cytokine balance and clinical phenotypes of acute-phase major depression. A total of 82 subjects including 42 patients with major depressive disorder and 40 healthy controls were recruited. Serum cytokine levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-10 were examined. Using ancova with age and body mass index (BMI) adjustments, there were no significant differences in serum IL-1β, TNF-α, and IL-10 levels between patients with major depressive disorder and healthy controls. However, using ancova with BMI adjustment only, the results showed that patients with major depressive disorder had significantly higher TNF-α levels than control subjects. In addition, using ancova with age and BMI adjustments, significantly higher serum IL-1β level and IL-1β/IL-10 ratio were noted in patients with melancholic features than patients with non-melancholic features. However, there were no significant differences in serum IL-1β, TNF-α and IL-10 levels between patients with and without suicide attempt. In conclusion, serum TNF-α, IL-1β level and IL-1β/IL-10 ratio might play an important role in the psychopathology of acute-phase major depressive disorder.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Many studies have demonstrated that depression is accompanied by activation of the immune/inflammatory system, including an acute-phase response indicated by changes in serum acute-phase protein, in Western countries.1–6 Recently, lower serum albumin (a negative acute-phase protein) and higher high-sensitivity C-reactive protein levels (a positive acute-phase protein, CRP) were also noted in Chinese ethnic background Taiwanese psychiatric patients with mood disorder than healthy controls.7,8 In addition, elevated CRP levels in patients with major depression and the changes in CRP levels might be related to changes in cytokine levels, particularly interleukin-6 (IL-6).4,6,9–11 Therefore, we were also interested in the relationships between cytokine levels and major depression in Chinese ethnic background Taiwanese.

Increased evidence has suggested that cytokine imbalance might play a role in the pathophysiology of major depression.12–18 Two general categories of cytokines, pro-inflammatory cytokines and anti-inflammatory cytokines, were applied to the studies of major depression. The former group consists of IL-1β, IL-6, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). They are mainly mediated by T-helper 1 (Th1) cells. The latter group includes IL-4, IL-5 and IL-10. They are mainly mediated by Th2 cells.19–21 Increased release of pro-inflammatory cytokines has been noted in patients with major depression.2,4,15,22–24 For Th2 cytokines, the results of IL-4 and IL-10 levels were not consistently replicated.16,22–27

In addition, Myint et al. observed a Th1 and Th2 cytokine imbalance in a subpopulation of depressed patients and indicated that tumor growth factor-β1 (TGF-β1) seemed to play a role in the pathophysiology of depression.16 In our knowledge, TGF-β1 could be a Th3 cytokine that has the ability to inhibit both Th1 and Th2 development and to regulate the balance between Th1 and Th2 cytokines.20,28,29 Furthermore, Rothermundt et al. and Kaestner et al. have demonstrated that melancholic and non-melancholic major depression have different immune patterns.30–32

Taken together, the aim of the present study was to investigate the relationships between Th1/Th2 cytokine imbalance and clinical phenotypes of acute-phase major depression in Chinese ethnic background Taiwanese subjects.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Subjects and design

This study was performed at Chang Gung Memorial Hospital (CGMH)–Kaohsiung Medical Center from December 2003 to July 2005. Institutional Review Board approval was obtained from the Ethics Committee of CGMH in Taiwan.

All subjects with major depression and healthy controls were assessed by the same psychiatrist using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID).33 The healthy controls were from the medical staff and students. All patients with major depressive disorder were psychiatric inpatients. The severity of depression was measured using the 17-item Hamilton Depression Rating Scale34 by the same psychiatrist. The determination of the clinical subtypes (melancholic or non-melancholic features) was done according to the DSM-IV criteria. Patients with suicide attempt was defined as having suicide attempt in the acute phase before admission to CGMH.

All subjects had blood pressure, chest X-ray, electrocardiogram (EKG) examinations and routine blood tests to exclude any chronic medical illness including heart, lung, liver, kidney and metabolic diseases. They were also required to be free of acute infections or allergic reactions and to avoid taking any medication for at least 2 weeks before the study (in acute phase). All participants gave written informed consent after receiving a full explanation of the study.

Laboratory data

Serum cytokine levels including IL-1β (Th1), TNF-α (Th1) and IL-10 (Th2) were investigated after the participants had fasted for at least 9 h. All cytokines were detected using ELISA kits (Amersham Biosciences, London, UK). All assays were carried out by the same operator at CGMH. The intra-assay and interassay variations were all <10%, respectively.

Statistical analyses

Participants were grouped into different diagnostic categories according to gender or diagnosis. Age and body mass index (BMI) have been reported to be related to cytokine levels.35,36 Data analysis was performed using analysis of covariance (ancova) with age and BMI adjustments for group mean differences in different groups. P < 0.05 was taken as being statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

Demographic data and serum cytokine levels

A total of 82 participants (27 male, 55 female) were recruited including 42 with major depression (12 male, 30 female) and 40 healthy controls (15 male, 25 female). Table 1 gives demographic data and serum cytokine levels for all participants.

Table 1.  Patient data and serum cytokine levels
 Sex (male /female)Age (years)BMI (kg/m2)Duration of illness (years)17 item HDRS scoreIL-1βTNF-α (pg/mL) (pg/mL)IL-10 (pg/mL)
  1. BMI, body mass index; HDRS, Hamilton Depression Rating Scale; IL, interleukin; TNF, tumor necrosis factor.

Major depression (n = 42)12/3038.0 ± 8.222.5 ± 4.42.9 ± 3.334.9 ± 4.24.2 ± 7.20.9 ± 2.424.7 ± 26.3
Healthy controls (n = 40)15/2531.4 ± 3.923.0 ± 3.0  12.4 ± 15.10.6 ± 3.712.2 ± 5.9

Using ancova with age and body mass index (BMI) adjustments, there were no significant differences in serum IL-1β (F = 1.195; d.f. = 1,80; P = 0.278), TNF-α (F = 2.382; d.f. = 1,80; P = 0.127) and IL-10 (F = 0.000; d.f. = 1,80; P = 0.987) levels between patients with major depressive disorder and healthy controls. However, age and BMI had interaction on the TNF-α level (F = 6.087; P = 0.016). Therefore, further data analysis was done with ancova with BMI adjustment only or ancova with age adjustment only, respectively. Using ancova with BMI adjustment only, the results showed that patients with major depressive disorder had significantly higher TNF-α levels than control subjects. (F = 4.135; d.f. = 1,80; P = 0.045).

Clinical phenotypes and serum cytokine levels in patients with major depression

Table 2 presents data for serum cytokine levels in depressive patients with different clinical phenotypes including patients with different clinical subtypes (melancholic or non-melancholic features) and patients with/without suicide attempt.

Table 2.  Serum cytokine levels of depressive patients with different clinical phenotypes at baseline
 Age (years)BMI (kg/m2)Duration of illness (years)17 item HDRS scoreIL-1βTNF-α (pg/mL) (pg/mL)IL-10 (pg/mL)
  1. BMI, body mass index; HDRS, Hamilton Depression Rating Scale; IL, Interleukin; TNF, tumor necrosis factor.

Clinical subtypes (n = 42)
 Melancholic feature (n = 25)40.2 ± 8.022.3 ± 3.22.3 ± 3.035.8 ± 4.05.8 ± 8.61.1 ± 2.624.5 ± 30.0
 Non- melancholic feature (n = 17)34.7 ± 7.622.9 ± 5.83.7 ± 3.633.5 ± 4.31.9 ± 3.70.7 ± 2.124.9 ± 21.2
Suicide attempts (n = 42)
 With suicide attempt (n = 11)33.3 ± 8.020.6 ± 3.53.1 ± 3.035.4 ± 3.95.6 ± 12.30.2 ± 0.717.4 ± 9.8
 Without suicide attempt (n = 31)39.6 ± 7.823.2 ± 4.52.8 ± 3.434.7 ± 4.43.8 ± 4.51.2 ± 2.827.2 ± 29.7

Using ancova with age and BMI adjustment, there were significantly higher serum IL-1β levels (F = 5.703; d.f. = 1, 40; P = 0.023) in patients with melancholic features than patients with non-melancholic features, but not for TNF-α (F = 1.571; d.f. = 1,40; P = 0.219) or IL-10 (F = 2.014; d.f. = 1,40; P = 0.165) levels. In addition, there were no significant differences in serum IL-1β (F = 0.172; d.f. = 1,40; P = 0.681), TNF-α (F = 0.032; d.f. = 1,40; P = 0.858) and IL-10 (F = 0.021, d.f. = 1,40; P = 0.884) levels between patients with and without suicide attempt.

Serum cytokine ratios (Th1/Th2) in all participants and clinical phenotypes in patients with major depression

Table 3 presents the serum cytokine ratios (Th1/Th2) for all participants. In the present study we defined Th1/Th2 as IL-1β/IL-10 and TNF-α/IL-10.

Table 3.  Th1/Th2 ratios and clinical phenotypes of major depression
 IL-1β/IL-10TNF-α/IL-10
  1. IL, interleukin; TNF, tumor necrosis factor.

Healthy controls (n = 40)1.11 ± 1.430.06 ± 0.39
Major depression (n = 42)0.21 ± 0.380.12 ± 0.33
Clinical subtypes (n = 42)
 Melancholic feature (n = 25)0.31 ± 0.460.17 ± 0.40
 Non- melancholic feature (n = 17)0.06 ± 0.150.06 ± 0.17
Suicide attempts (n = 42)
 With suicide attempt (n = 11)0.26 ± 0.530.02 ± 0.08
 Without suicide attempt (n = 31)0.19 ± 0.330.16 ± 0.37

Using ancova with age and BMI adjustments, there were no significant differences in IL-1β/IL-10 (F = 1.522; d.f. = 1,80; P = 0.221) and TNF-α/IL-10 (F = 2.062; d.f. = 1,80; P = 0.155) ratios between patients with major depression and healthy controls.

Using ancova with age and BMI adjustment, significantly higher serum IL-1β/IL-10 (F = 6.556; d.f. = 1,40; P = 0.015) ratio was noted in patients with melancholic features than in patients with non-melancholic features. However, there was no significant difference in TNF-α/IL-10 (F = 0.217; d.f. = 1,40; P = 0.644) ratio between patients with melancholic features and those with non-melancholic features. In addition, there were no significant differences in serum IL-1β/IL-10 (F = 0.136; d.f. = 1,40; P = 0.715) and TNF-α/IL-10 (F = 0.038; d.f. = 1,40; P = 0.847) ratios between patients with and without suicide attempt.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

One of the most important finding in the present study was that there were significantly higher TNF-α levels in patients with major depression than in control groups. However, no significant differences were noted in levels of IL-1β and IL-10 between these two groups. This means that TNF-α might play a more important role in the psychopathology of major depression than other cytokines. The role of TNF-α in asthma and other airway disease has been discussed in many papers including in clinical and basic studies.37–39 The TNF-α concentration is higher than normal in multiple sclerosis patients40 and in Alzheimer's patients.41 The relationships between cytokine and major depression have been explored recently.15,16 Furthermore, Simen et al. have noted the role of TNF-α signaling in mediating depression- and anxiety-like behavior in animal studies.42

In addition to the relationships in serum cytokine levels between major depression and healthy controls, some studies have investigated the relationships in Th1/Th2 ratios between major depression and healthy controls.16,23,24 Myint et al. found that the plasma IFN-γ/IL-4 ratio (Th1/Th2 ratio) and IFN-γ/TGF-β1 ratio (Th1/Th3 ratio) were higher in depressed patients than in healthy controls and suggested that antidepressant treatment could affect the Th1/Th2 balance through the action of TGF-β1.16 In the present study Th1/Th2 ratios could not be used to distinguish the differences between patients with major depression and control subjects.

Another important finding of the present study is that of the significantly higher serum IL-1β level and IL-1β/IL-10 ratio in patients with melancholic features compared to patients with non-melancholic features. These analytical results also support the hypothesis that melancholic and non-melancholic major depression might have different immune patterns. In past studies, Rothermundt et al. have demonstrated that melancholic and non-melancholic major depression had different immune patterns, including that melancholic patients had decreased production of IL-2, IFN-γ and IL-10 during the acute stage of disease.30,31 Further, Kaestner et al. found that melancholic patients had an activation of the hypothalamus–pituitary–adrenal (HPA) axis in the acute stage with partial normalization upon remission but no signs of inflammation, and that non-melancholic patients had signs of inflammation in the acute phase and the function of the HPA axis was normal.32 Furthermore, Kaestner et al. also found that non-melancholic patients had a significantly higher IL-1β level upon admission than control and melancholic patients.32 However, in the present study it was found that melancholic patients had a significantly higher IL-1β level than non-melancholic patients. The reason for and mechanism of this contrast are still unknown. In future, the relationships between serum cytokine levels and subtypes of major depression and the interactions between HPA axis, immune axis and serotonergic system will need to be further explored.43

In addition, TGF-β1 could regulate the imbalance between Th1 and Th2 cytokines and has been proposed to play an important role in maintaining tolerance including the central nervous system.16,44 It is possible that the role of the IL-1β/IL-10 ratio (Th1/Th2 cytokine imbalance) occurs not only in oral immunity,44 but also in the clinical subtypes of major depression (melancholic and non-melancholic features). Marques-Deak et al. have recently investigated some cytokine profiles in women with different subtypes of major depressive disorder (melancholic vs non-melancholic; acute vs chronic; severe vs moderate; and episodic vs recurrent presentations).45

In conclusion, the present study shows that serum TNF-α level, IL-1β level and IL-1β/IL-10 ratio might play an important role in the psychopathology of major depressive disorder in the acute phase.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES

This work was supported by a clinical research grant from the National Science Council (NSC93-2314-B-182A-204) in Taiwan. In addition we acknowledge laboratory support by Rong-Fu Chen PhD in the Department of Medical Research, Chang Gung Memorial Hospital–Kaohsiung Medical Center, Taiwan.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. REFERENCES
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