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Serum haptoglobin levels in patients with melancholic and nonmelancholic major depression
Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 944–947
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Serum haptoglobin levels in patients with melancholic and nonmelancholic major depression Murat Erdem a, Cemil Celik a,⁎, Tuncer Cayci b, Barbaros Ozdemir a, Yasemin Gulcan Kurt b, Emin Ozgur Akgul b, Halil Yaman b, Adem Balikci c, Ozcan Uzun a a b c
Gulhane Military Medical Academy, Department of Psychiatry, Ankara, Turkey Gulhane Military Medical Academy, Department of Biochemistry, Ankara, Turkey Samsun Military Hospital, Department of Psychiatry, Samsun, Turkey
a r t i c l e
i n f o
Article history: Received 15 October 2010 Received in revised form 11 January 2011 Accepted 11 January 2011 Available online 20 January 2011 Keywords: Haptoglobulin Melancholic major depression Nonmelancholic major depression
a b s t r a c t Background: Major depression (MD) is accompanied by systemic immune activation or an inflammatory response with the involvement of phagocytic cells, T cell activation, B cell proliferation, and an acute phase response with increased levels of positive and decreased levels of negative acute-phase proteins. In this study, we aimed to determine any differences in serum haptoglobin (Hp) concentrations among patients with melancholic and nonmelancholic MD and the healthy controls. Methods: This study involved 125 male patients who were admitted to the Department of Psychiatry, Gulhane Military Medical Academy (GMMA), in Ankara, Turkey. They were diagnosed with MD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and agreed to participate in the study. The melancholic group consisted of 37 patients and the nonmelancholic group had 45 patients. A healthy control group of 40 subjects was selected from the staff of GMMA. These subjects had not had any lifetime psychiatric diagnosis or psychiatric treatment in their medical histories. Peripheral venous blood samples were obtained from the patients and the control group for a complete blood count, routine biochemistry, and the detection of serum Hp levels. Results: There was no statistically significant difference among the melancholic MD, the nonmelancholic MD, and the healthy control groups in terms of age, level of education, and gender. Serum Hp concentrations are significantly higher in melancholic patients as compared with non-melancholic depressed patients and controls. However, there was no statistically significant difference between the nonmelancholic MD and the control group in terms of Hp concentrations. Conclusion: The results of this study are important in terms of showing different serum Hp concentrations in patients with melancholic and nonmelancholic MD. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Depression has been associated with the activation of the immune system described by higher levels of pro-inflammatory cytokines and positive acute-phase proteins (Zorrilla et al., 2001, Scheipers et al., 2005). These cytokines were produced by monocytes and exerted farreaching effects on the human body. They increase body temperature and stimulate hepatocytes and, consequently, acute-phase
Abbreviations: Hp, Haptoglobulin; MD, Major Depression; GMMA, Gulhane Military Medical Academy; DSM-IV, Diagnostic and Statistical Manual Of Mental Disorders; AP, Acute-phase; Hb, Hemoglobin; SCID-I, Structured Clinical Interview for The DSM-IV Axis I Disorders; CRP, C-reactive protein; HDRS, Hamilton Depression Rating Scale; IL, Interleukin; TNF-α, Tumor necrosis factor-alpha. ⁎ Corresponding author at: Department of Psychiatry, Gulhane Military Medical Academy, Etlik-06018, Ankara, Turkey. Tel.: + 90 312 304 4501; fax: + 90 312 304 4507. E-mail address: [email protected] (C. Celik). 0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2011.01.009
proteins such as C-reactive protein (CRP), haptoglobin (Hp), and α-2-macroglobulin are produced. Serum Hp is one of these important proteins. Some studies on the genetics of depression have focused on the genes associated with serum Hp (Maes et al., 1994a). Serum Hp is an α-sialoglycoprotein that has hemoglobin (Hb)-binding capacity (Bowman, 1993). The bestknown biological function of serum Hp is capturing Hb to prevent both iron loss and kidney damage during hemolysis. Serum Hp is also a positive AP protein (Giblett, 1968). In the depressive cases, results for haptoglobin levels are generally consistent (Joyce et al., 1992, Maes et al., 1992, Maes et al., 1994b, Song et al., 1994, Seidel et al., 1995, Maes et al., 1997). Melancholic depression is a type of depression that 1) has not been precipitated by stress, 2) has a biological etiology, 3) goes with unresponsiveness to environmental events, 4) responds to somatic therapies but not psychotherapy, 5) is seen in patients without personality pathology, and 6) is characterized by a special symptom
M. Erdem et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 944–947
pattern (Rush and Weissenburger, 1994). Although many studies have shown elevated acute-phase proteins in MD patients, studies examining whether differences exist between melancholic and nonmelancholic depression in terms of acute-phase response are very few and these studies were carried out with small samples. In this study, we aimed to determine whether there are differences among serum Hp concentrations in patients with melancholic and nonmelancholic depression and in healthy controls. 2. Material and methods This study involved 125 male patients who were admitted to the department of Psychiatry, Gulhane Military Medical Academy (GMMA), Ankara, Turkey. These patients were diagnosed as major depressive disorder (DSM IV 296.2 and 296.3) in a structured clinical interview for DSM-IV Axis I Disorders (SCID-I). The SCID-I was administered by two trained psychiatrists. Fourteen patients who were diagnosed as psychotic, atypical, catatonic and postpartum depression were excluded from the study. Twenty-nine other patients who had other medical diseases or a history of psychotropic drugs or alcohol/substance abuse within the previous six weeks were excluded from the study. The melancholic subgroup was identified according to DSM IV criteria (melancholic features, SCID). The melancholic group consisted of 37 patients, and the nonmelancholic group had 45 patients. The healthy control group was selected from the staff of GMMA. These 40 subjects had not had any lifetime psychiatric diagnosis or psychiatric treatment in their medical histories. The study was approved by The Local Research Ethical Committee at GMMA, and informed written consent was obtained from all participants. The participants' medical histories were acquired and physical examinations were performed. Patients were screened for acute infectious diseases by measuring body temperature, erythrocyte sedimentation rate, CRP, urine analyses and urinary culture. Exclusion criteria were any additional Axis I or Axis II DSM-IV diagnosis; pregnancy; acute or chronic infections within the past month; autoimmune, allergic, neoplastic, or endocrine diseases (thyroid and other endocrine dsyfunctions); and other acute physical disorders, including surgery or infarction of the heart or brain within the previous three months. In the last six months, patients who were exposed to any drug, including nonsteroidal anti-inflammatory drugs, or used of oral contraceptives were also excluded. The healthy volunteers were also interviewed and, in addition to the above exclusion criteria, those with no lifetime or current diagnosis of any psychiatric disorders were enrolled as the control group. All patients abstained from taking any psychoactive medication for at least six weeks before the trials. Sociodemographic data (age, gender, level of education, and marital status) and clinical features of all participants were examined by using a data query form. A major depressive episode was diagnosed with the Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID-I) form. The SCID-I is a structured clinical interview form developed by First et al. (1997). It is used for the diagnosis of DSM-IV Axis I disorders. The validity and reliability studies of the Turkish form were conducted by Ozkurkcugil et al. (1999). The severity of the depression was evaluated by using the 17-item Hamilton Depression Rating Scale (HDRS). The validity and reliability studies of Turkish form were conducted by Akdemir et al. (1996). Peripheral venous blood samples were obtained from all patients and the healthy controls for complete blood counts, routine biochemistry, and measurements of serum Hp levels. Serum blood samples were taken between 8:00 and 11:00 a.m. after subjects had fasted overnight for 12 h. A fasting blood sample was collected from all subjects. Whole blood was collected into tubes without an anticoagulant (for preparation of the serum). The serum fraction was obtained by centrifugation (2000 ×g, 10 min, 4 °C) after storing the whole blood at room temperature for ≈1 h. Sera were stored at − 80 °C until analyses. All the analyses were performed in department of medical
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biochemistry GMMA. Serum Hp concentrations were quantified with Beckman-Array 360 Nephelometers (Beckman Instruments, CA, USA) using Beckman Array® system reagents. Serum Hp results were expressed as nmol/L. 2.1. Statistical analysis Statistical analyses were performed by using SPSS 15.0 (SPSS Inc., Chicago, IL, USA) statistical package program. For the comparison of the quantitative data, one-way ANOVA test was used if the parametric conditions were met. Post hoc evaluation was made with Tukey's test. For comparison of qualitative data, X2 test was used. The Kruskal– Wallis test was used for the comparison of more than two groups. The Pearson correlation test was used to evaluate the association between two variables. The ROC curve for serum Hp concentrations was used to discriminate melancholic MD from nonmelancholic MD and healthy controls. The rate was set to α = 0.05 and p values equal to or lower than this value were considered as statistically significant. All data was presented as the mean ± standard deviation (SD). 3. Results In both the MD and the control groups, the results of the complete blood counts and routine biochemical analyses were within the normal reference ranges. Sociodemographic data belonging to all groups is presented in Table 1. There was no statistically significant difference among the melancholic MD, the nonmelancholic MD and the healthy control groups in terms of age, level of education, and gender. The HDRS scores in the melancholic MD group were higher than for the nonmelancholic MD group. In the melancholic MD group, serum Hp concentrations were higher than in the nonmelancholic MD and the control groups (159.2 ± 71.0, 95.8 ± 45.7 and, 96.6 ± 34.1 nmol/L, respectively) (both p b 0.001) (Table 1). However, there were no statistically significant difference between the nonmelancholic MD and the control group. There is a correlation between serum Hp concentrations and HDRS scores after controlling age, sex, and education level (r = 0.33, p = 0.003). Fig. 1 shows serum Hp levels of the melancholic MD, nonmelancholic MD, and control groups. It was found that 18 patients (48.7%) in the melancholic MD group, 5 patients (11.1%) in the nonmelancholic MD group, and 1 patient (2.5%) in the control group had a haptoglobin level at or above the normal serum Hp level of 150 ng/dL. The serum Hp threshold for the prediction of melancholic MD was 113 nmol/L. For this value, the sensitivity and specificity values were
Table 1 Sociodemographic features, Hamilton depression scores (HDRS) and serum haptoglobin concentrations in the all groups. Variables
Nonmelancholic Healthy Melancholic major depression major depression control (n = 40) (n = 45) (n = 37)
Statistics
Age (years)
35.6 ± 6.2
34.0 ± 6.6
33.7 ± 3.9
Education level (years) Gender (n, %) Female Male Serum haptoglobin (nmol/L) HDRS values
9.7 ± 3.2
9.0 ± 3.9
9.6 ± 3.7
F = 1.1 p = 0.32 F = 0.52 p = 0.60
14 (37.8) 23 (62.2) 159.2 ± 71.0
21 (46.7) 24 (53.3) 95.8 ± 45.7
16 (40) 24 (60) 96.6 ± 34.1
30.1 ± 6.0
23.9 ± 4.2
–
⁎X2 = 0.73 p = 0.69 ⁎⁎X2 = 23.9 p b 0.001 t = 5.57 p b 0.001
All data were presented as the mean ± SD and%. F: ANOVA test value. t: Student t test value. ⁎ X2: Chi-square test value. ⁎⁎ X2: Kruskal Wallis test value.
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M. Erdem et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 944–947
400.00
serum haptoglobin level
300.00
200.00
100.00
0.00
melancholic
nonmelancholic
control
group Fig. 1. Serum haptoglobin level in melancholic/nonmelancholic depression and control groups.
75.7% and 73.3%, respectively. The area under the ROC curve (AUC) for serum Hp was 0.784 (p b 0.001) (CI = 0.684–0.884) (Fig. 2). 4. Discussion In this study, we found that melancholic MD patients' serum Hp concentrations were higher than nonmelancholic MD patients and the healthy controls. At the same time, there was a correlation between depression severity and serum Hp concentrations among the MD patients. In a relatively large sample, our results are important in
ROC Curve 1,0
Sensitivity
0,8
0,6
0,4
0,2
0,0 0,0
0,2
0,4
0,6
0,8
1,0
1-Specificity Fig. 2. ROC curve serum Hp level for discriminating melancholic depression.
terms of showing different serum Hp concentrations in melancholic and nonmelancholic MD patients. One of the most accepted classifications for depression subgroups is their separation as either melancholic or nonmelancholic (Zimmerman et al., 1986). Melancholic MD is not only a more severe form of nonmelancholic MD, but it is also characterized by the loss of pleasure in almost all activities. There is a lack of response to the usual pleasurable stimuli, and the depressed mood is experienced as a feeling distinct from that experienced after a major loss. At the same time, a feeling of excessive or inappropriate guilt may exist. In melancholia, depression is regularly worse in the morning, and waking early in the morning in a depressive mood also occurs. Patients may suffer from marked psychomotor retardation or agitation and significant weight loss (Rush and Weissenburger, 1994). Maes et al. (1993a) found that the vegetative symptoms of major depression (insomnia and reduced locomotion) were correlated with higher levels of haptoglobulinemia but not with mood state. In one study, serum IL 1-beta, IL-1 receptor antagonist levels were higher in the nonmelancholic MD group than in the melancholic MD group (Kaestner et al., 2005). Rothermundt et al. (2001a) found high levels of leukocyte, lymphocyte, and Natural Killer cell levels in patients with non-melancholic MD and higher IL-2, IL-10 and INF-γ levels in patients with melancholic MD. Marques-Deak et al. (2007) found no difference at IL 1-beta, IL-6, interferon gamma levels among groups according to the type of depression (melancholic–nonmelancholic), process (acute and chronic), severity (heavy and moderate), and course (episodic and recurrent) in 46 untreated female patients with MD. Only a few studies have compared the serum Hp levels in melancholic and nonmelancholic patients. Rothermundt et al. (2001b) showed that there were no differences in serum Hp concentrations among three groups (melancholic MD, non-melancholic MD, and healthy individuals). In two separate studies, Maes et al. (1993b,c) found that in patients with MD, serum Hp levels were higher than in the minor depression and the control group, but there were no differences between the melancholic and nonmelancholic MD groups. In the study
M. Erdem et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 944–947
by Maes et al., the melancholic MD group consisted of 14 and 10 and the nonmelancholic MD group consisted of 29 and 7 patients, respectively. As well as our smaller sample size, the average ages of the patients in the melancholic and nonmelancholic MD groups in our study (35.6 and 34.0, respectively) were lower than ages of both samples of Maes's study (52.6 and 47.1, and 54.8 and 51.7, respectively), which may have caused the results to differ. Factors such as age, sex, diet, circadian rhythm, or the Hp phenotype may affect the serum Hp level (Maes et al., 1993a). Another reason for the differences may be the duration of the disease and the number of depressive episodes. However, neither the duration of disease nor the number of depressive episode has been evaluated in both studies. In previous studies, Celik et al. (2010) and Danner et al. (2003) have shown that cellular and acute-phase response will be affected by number of depressive episode in patients with MD. Some studies have shown that changes in the immune system may be related to the severity of depression in MD patients (Stein et al., 1987, Maes et al., 1991). According to the inflammation hypothesis in MD, the disease is generally associated with a global inflammatory reaction and the severity of the depressive symptoms is positively correlated with inflammation markers (Maes, 1995). Our findings support this hypothesis and the severity of the disease was related to the acute-phase response. An important limitation of our study was the cellular immune response was not evaluated. Another limitation was that previous depressive episodes were not evaluated. Further studies are needed to compare both humoral and cellular immune responses in patients with MD. In conclusion, this study demonstrated that the severity of depression is related to acute-phase responses in patients with melancholic and nonmelancholic MD. Further studies are needed to evaluate other immune response indicators and hypothalamic– pituitary–adrenal axis properties in patients with melancholic and nonmelancholic MD. In the future, it may be interesting and appropriate to investigate changes in indicators of the immune system (e.g. Hp) after treatment by properly designed studies. References Akdemir A, Orsel S, Dag I. Hamilton depresyon derecelendirme olceginin gecerliligi, guvenilirligi ve klinikte kullanimi. 3P Dergisi 1996;4:251–9. Bowman BH. Haptoglobin. In: Bowman BH, editor. Hepatic plasma proteins. San Diego: Academic Press; 1993. p. 159–67. Celik C, Erdem M, Caycı T, Ozdemir B, Ozgur Akgul E, Kurt YG, et al. The association between serum levels of neopterin and number of depressive episodes of major depression. Prog Neuropsychopharmacol Biol Psychiatry 2010;34(2):372–5. Danner M, Kasl SV, Abramson JL, Vaccarino V. Association between depression and elevated C-reactive protein. Psychosom Med 2003;65:347–56. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV axis I disorders (SCID-I), clinical version. Washington D.C: American Psychiatric Press, Inc; 1997. Giblett ER. The haptoglobin system. Ser Haematol 1968;1:3-20.
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Joyce PR, Hawes CR, Mulder RT, Sellman JD, Wilson DA, Boswell DR. Elevated levels of acute phase proteins in major depression. Biol Psychiatry 1992;32:1035–41. Kaestner F, Hettich M, Peters M, Sibrowski W, Hetzel G, Ponath G, et al. Different activation patterns of proinflammatory cytokines in melancholic and nonmelancholic major depression are associated with HPA axis activity. J Affect Disord 2005;87(2–3):305–11. Maes M, Bosman E, Suy E, Minner B, Raus J. A further exploration of the relationships between immune parameters and the HPA-axis activity in depressed patients. Psychol Med 1991;21:313–20. Maes M, Scharpe S, Van Grootel L, Uyttenbroeck W, Cooreman W, Cosyns P, et al. Higher alpha1-antitrypsin, haptoglobin, ceruloplasmin and lower retinol binding protein plasma levels during depression: further evidence for the existence of an inflammatory response during that illness. J Affect Disord 1992;24:183–92. Maes M, Meltzer HY, Scharpe S, Cooreman W, Uyttenbroeck W, Suy E. Psychosomatic retardation, anorexia, weight loss, sleep disturbances, and loss of energy: psychopathological correlates of hyperhaptoglobulinemia during major depression. Psychiatry Res 1993a;47:229–41. Maes M, Scharpe S, Meltzer HY, Bosmans E, Suy E, Calabrese J, et al. Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic– pituitary–adrenal axis in severe depression. Psychiatry Res 1993b;49:11–27. Maes M, Scharpe S, Meltzer HY, Cosyns P. Relationships between increased haptoglobin plasma levels and activation of cell-mediated immunity in depression. Biol Psychiatry 1993c;34:690–701. Maes M, Delanghe J, Scharpé S, Meltzer HY, Cosyns P, Suy E, et al. Haptoglobin phenotypes and gene frequencies in unipolar major depression. Am J Psychiatry 1994a;151:112–6. Maes M, Scharpé S, Cosyns P, Meltzer H. Relationships between basal hypothalamic– pituitary–adrenal axis activity and plasma haptoglobin levels in depression. J Psychiatr Res 1994b;28:123–34. Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 1995;19:11–38. Maes M, Delanghe J, Ranjan R, Meltzer HY, Cooremans W, Scharpe S. Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res 1997;66:1-11. Marques-Deak AH, Neto FL, Dominguez WV, Solis AC, Kurcgant D, Sato F, et al. Cytokine profiles in women with different subtypes of major depressive disorder. J Psychiatr Res 2007;41:152–9. Ozkurkcugil A, Aydemir O, Yildiz M, Esen Danaci A, Koroglu E. DSM-IV eksen I bozukluklari icin yapilandirilmis klinik gorusmenin Turkceye uyarlanmasi ve guvenilirlik calismasi. Ilac ve Tedavi Dergisi 1999;12:233–6. Rothermundt M, Arolt V, Fenker J, Gutbrodt H, Peters M, Kirchner H. Different immune patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci 2001a;251:90–7. Rothermundt M, Arolt V, Peters M, Gutbrodt H, Fenker J, Kersting A, et al. Inflammatory markers in major depression and melancholia. J Affect Disord 2001b;63:93-102. Rush AJ, Weissenburger JE. Melancholic symptom features and DSM-IV. Am J Psychiatry 1994;151:489–98. Scheipers OJG, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:201–17. Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H. Cytokine production and serum proteins in depression. Scand J Immunol 1995;41:534–8. Song C, Dinan T, Leonard BE. Changes in immunoglobulin, complement and acute phase protein levels in the depression associated with immune activation? J Affect Disord 1994;30:283–8. Stein M, Schleifer SJ, Keller SE. Psychoimmunology in clinical psychiatry. Psychiatric update: The American psychiatric association annual review; 1987. Zimmerman M, Coryell W, Pfohl B, Stangl D. The validity of four definitions of endogenous depression. Arch Gen Psychiatry 1986;43 234–4. Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A, et al. The relationship of depression and stressors to immunological assays: A meta-analytic review. Brain Behav Immun 2001;15:199–226.
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
Serum haptoglobin levels in patients with melancholic and nonmelancholic major depression Murat Erdem a, Cemil Celik a,⁎, Tuncer Cayci b, Barbaros Ozdemir a, Yasemin Gulcan Kurt b, Emin Ozgur Akgul b, Halil Yaman b, Adem Balikci c, Ozcan Uzun a a b c
Gulhane Military Medical Academy, Department of Psychiatry, Ankara, Turkey Gulhane Military Medical Academy, Department of Biochemistry, Ankara, Turkey Samsun Military Hospital, Department of Psychiatry, Samsun, Turkey
a r t i c l e
i n f o
Article history: Received 15 October 2010 Received in revised form 11 January 2011 Accepted 11 January 2011 Available online 20 January 2011 Keywords: Haptoglobulin Melancholic major depression Nonmelancholic major depression
a b s t r a c t Background: Major depression (MD) is accompanied by systemic immune activation or an inflammatory response with the involvement of phagocytic cells, T cell activation, B cell proliferation, and an acute phase response with increased levels of positive and decreased levels of negative acute-phase proteins. In this study, we aimed to determine any differences in serum haptoglobin (Hp) concentrations among patients with melancholic and nonmelancholic MD and the healthy controls. Methods: This study involved 125 male patients who were admitted to the Department of Psychiatry, Gulhane Military Medical Academy (GMMA), in Ankara, Turkey. They were diagnosed with MD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and agreed to participate in the study. The melancholic group consisted of 37 patients and the nonmelancholic group had 45 patients. A healthy control group of 40 subjects was selected from the staff of GMMA. These subjects had not had any lifetime psychiatric diagnosis or psychiatric treatment in their medical histories. Peripheral venous blood samples were obtained from the patients and the control group for a complete blood count, routine biochemistry, and the detection of serum Hp levels. Results: There was no statistically significant difference among the melancholic MD, the nonmelancholic MD, and the healthy control groups in terms of age, level of education, and gender. Serum Hp concentrations are significantly higher in melancholic patients as compared with non-melancholic depressed patients and controls. However, there was no statistically significant difference between the nonmelancholic MD and the control group in terms of Hp concentrations. Conclusion: The results of this study are important in terms of showing different serum Hp concentrations in patients with melancholic and nonmelancholic MD. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Depression has been associated with the activation of the immune system described by higher levels of pro-inflammatory cytokines and positive acute-phase proteins (Zorrilla et al., 2001, Scheipers et al., 2005). These cytokines were produced by monocytes and exerted farreaching effects on the human body. They increase body temperature and stimulate hepatocytes and, consequently, acute-phase
Abbreviations: Hp, Haptoglobulin; MD, Major Depression; GMMA, Gulhane Military Medical Academy; DSM-IV, Diagnostic and Statistical Manual Of Mental Disorders; AP, Acute-phase; Hb, Hemoglobin; SCID-I, Structured Clinical Interview for The DSM-IV Axis I Disorders; CRP, C-reactive protein; HDRS, Hamilton Depression Rating Scale; IL, Interleukin; TNF-α, Tumor necrosis factor-alpha. ⁎ Corresponding author at: Department of Psychiatry, Gulhane Military Medical Academy, Etlik-06018, Ankara, Turkey. Tel.: + 90 312 304 4501; fax: + 90 312 304 4507. E-mail address: [email protected] (C. Celik). 0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2011.01.009
proteins such as C-reactive protein (CRP), haptoglobin (Hp), and α-2-macroglobulin are produced. Serum Hp is one of these important proteins. Some studies on the genetics of depression have focused on the genes associated with serum Hp (Maes et al., 1994a). Serum Hp is an α-sialoglycoprotein that has hemoglobin (Hb)-binding capacity (Bowman, 1993). The bestknown biological function of serum Hp is capturing Hb to prevent both iron loss and kidney damage during hemolysis. Serum Hp is also a positive AP protein (Giblett, 1968). In the depressive cases, results for haptoglobin levels are generally consistent (Joyce et al., 1992, Maes et al., 1992, Maes et al., 1994b, Song et al., 1994, Seidel et al., 1995, Maes et al., 1997). Melancholic depression is a type of depression that 1) has not been precipitated by stress, 2) has a biological etiology, 3) goes with unresponsiveness to environmental events, 4) responds to somatic therapies but not psychotherapy, 5) is seen in patients without personality pathology, and 6) is characterized by a special symptom
M. Erdem et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 944–947
pattern (Rush and Weissenburger, 1994). Although many studies have shown elevated acute-phase proteins in MD patients, studies examining whether differences exist between melancholic and nonmelancholic depression in terms of acute-phase response are very few and these studies were carried out with small samples. In this study, we aimed to determine whether there are differences among serum Hp concentrations in patients with melancholic and nonmelancholic depression and in healthy controls. 2. Material and methods This study involved 125 male patients who were admitted to the department of Psychiatry, Gulhane Military Medical Academy (GMMA), Ankara, Turkey. These patients were diagnosed as major depressive disorder (DSM IV 296.2 and 296.3) in a structured clinical interview for DSM-IV Axis I Disorders (SCID-I). The SCID-I was administered by two trained psychiatrists. Fourteen patients who were diagnosed as psychotic, atypical, catatonic and postpartum depression were excluded from the study. Twenty-nine other patients who had other medical diseases or a history of psychotropic drugs or alcohol/substance abuse within the previous six weeks were excluded from the study. The melancholic subgroup was identified according to DSM IV criteria (melancholic features, SCID). The melancholic group consisted of 37 patients, and the nonmelancholic group had 45 patients. The healthy control group was selected from the staff of GMMA. These 40 subjects had not had any lifetime psychiatric diagnosis or psychiatric treatment in their medical histories. The study was approved by The Local Research Ethical Committee at GMMA, and informed written consent was obtained from all participants. The participants' medical histories were acquired and physical examinations were performed. Patients were screened for acute infectious diseases by measuring body temperature, erythrocyte sedimentation rate, CRP, urine analyses and urinary culture. Exclusion criteria were any additional Axis I or Axis II DSM-IV diagnosis; pregnancy; acute or chronic infections within the past month; autoimmune, allergic, neoplastic, or endocrine diseases (thyroid and other endocrine dsyfunctions); and other acute physical disorders, including surgery or infarction of the heart or brain within the previous three months. In the last six months, patients who were exposed to any drug, including nonsteroidal anti-inflammatory drugs, or used of oral contraceptives were also excluded. The healthy volunteers were also interviewed and, in addition to the above exclusion criteria, those with no lifetime or current diagnosis of any psychiatric disorders were enrolled as the control group. All patients abstained from taking any psychoactive medication for at least six weeks before the trials. Sociodemographic data (age, gender, level of education, and marital status) and clinical features of all participants were examined by using a data query form. A major depressive episode was diagnosed with the Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID-I) form. The SCID-I is a structured clinical interview form developed by First et al. (1997). It is used for the diagnosis of DSM-IV Axis I disorders. The validity and reliability studies of the Turkish form were conducted by Ozkurkcugil et al. (1999). The severity of the depression was evaluated by using the 17-item Hamilton Depression Rating Scale (HDRS). The validity and reliability studies of Turkish form were conducted by Akdemir et al. (1996). Peripheral venous blood samples were obtained from all patients and the healthy controls for complete blood counts, routine biochemistry, and measurements of serum Hp levels. Serum blood samples were taken between 8:00 and 11:00 a.m. after subjects had fasted overnight for 12 h. A fasting blood sample was collected from all subjects. Whole blood was collected into tubes without an anticoagulant (for preparation of the serum). The serum fraction was obtained by centrifugation (2000 ×g, 10 min, 4 °C) after storing the whole blood at room temperature for ≈1 h. Sera were stored at − 80 °C until analyses. All the analyses were performed in department of medical
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biochemistry GMMA. Serum Hp concentrations were quantified with Beckman-Array 360 Nephelometers (Beckman Instruments, CA, USA) using Beckman Array® system reagents. Serum Hp results were expressed as nmol/L. 2.1. Statistical analysis Statistical analyses were performed by using SPSS 15.0 (SPSS Inc., Chicago, IL, USA) statistical package program. For the comparison of the quantitative data, one-way ANOVA test was used if the parametric conditions were met. Post hoc evaluation was made with Tukey's test. For comparison of qualitative data, X2 test was used. The Kruskal– Wallis test was used for the comparison of more than two groups. The Pearson correlation test was used to evaluate the association between two variables. The ROC curve for serum Hp concentrations was used to discriminate melancholic MD from nonmelancholic MD and healthy controls. The rate was set to α = 0.05 and p values equal to or lower than this value were considered as statistically significant. All data was presented as the mean ± standard deviation (SD). 3. Results In both the MD and the control groups, the results of the complete blood counts and routine biochemical analyses were within the normal reference ranges. Sociodemographic data belonging to all groups is presented in Table 1. There was no statistically significant difference among the melancholic MD, the nonmelancholic MD and the healthy control groups in terms of age, level of education, and gender. The HDRS scores in the melancholic MD group were higher than for the nonmelancholic MD group. In the melancholic MD group, serum Hp concentrations were higher than in the nonmelancholic MD and the control groups (159.2 ± 71.0, 95.8 ± 45.7 and, 96.6 ± 34.1 nmol/L, respectively) (both p b 0.001) (Table 1). However, there were no statistically significant difference between the nonmelancholic MD and the control group. There is a correlation between serum Hp concentrations and HDRS scores after controlling age, sex, and education level (r = 0.33, p = 0.003). Fig. 1 shows serum Hp levels of the melancholic MD, nonmelancholic MD, and control groups. It was found that 18 patients (48.7%) in the melancholic MD group, 5 patients (11.1%) in the nonmelancholic MD group, and 1 patient (2.5%) in the control group had a haptoglobin level at or above the normal serum Hp level of 150 ng/dL. The serum Hp threshold for the prediction of melancholic MD was 113 nmol/L. For this value, the sensitivity and specificity values were
Table 1 Sociodemographic features, Hamilton depression scores (HDRS) and serum haptoglobin concentrations in the all groups. Variables
Nonmelancholic Healthy Melancholic major depression major depression control (n = 40) (n = 45) (n = 37)
Statistics
Age (years)
35.6 ± 6.2
34.0 ± 6.6
33.7 ± 3.9
Education level (years) Gender (n, %) Female Male Serum haptoglobin (nmol/L) HDRS values
9.7 ± 3.2
9.0 ± 3.9
9.6 ± 3.7
F = 1.1 p = 0.32 F = 0.52 p = 0.60
14 (37.8) 23 (62.2) 159.2 ± 71.0
21 (46.7) 24 (53.3) 95.8 ± 45.7
16 (40) 24 (60) 96.6 ± 34.1
30.1 ± 6.0
23.9 ± 4.2
–
⁎X2 = 0.73 p = 0.69 ⁎⁎X2 = 23.9 p b 0.001 t = 5.57 p b 0.001
All data were presented as the mean ± SD and%. F: ANOVA test value. t: Student t test value. ⁎ X2: Chi-square test value. ⁎⁎ X2: Kruskal Wallis test value.
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400.00
serum haptoglobin level
300.00
200.00
100.00
0.00
melancholic
nonmelancholic
control
group Fig. 1. Serum haptoglobin level in melancholic/nonmelancholic depression and control groups.
75.7% and 73.3%, respectively. The area under the ROC curve (AUC) for serum Hp was 0.784 (p b 0.001) (CI = 0.684–0.884) (Fig. 2). 4. Discussion In this study, we found that melancholic MD patients' serum Hp concentrations were higher than nonmelancholic MD patients and the healthy controls. At the same time, there was a correlation between depression severity and serum Hp concentrations among the MD patients. In a relatively large sample, our results are important in
ROC Curve 1,0
Sensitivity
0,8
0,6
0,4
0,2
0,0 0,0
0,2
0,4
0,6
0,8
1,0
1-Specificity Fig. 2. ROC curve serum Hp level for discriminating melancholic depression.
terms of showing different serum Hp concentrations in melancholic and nonmelancholic MD patients. One of the most accepted classifications for depression subgroups is their separation as either melancholic or nonmelancholic (Zimmerman et al., 1986). Melancholic MD is not only a more severe form of nonmelancholic MD, but it is also characterized by the loss of pleasure in almost all activities. There is a lack of response to the usual pleasurable stimuli, and the depressed mood is experienced as a feeling distinct from that experienced after a major loss. At the same time, a feeling of excessive or inappropriate guilt may exist. In melancholia, depression is regularly worse in the morning, and waking early in the morning in a depressive mood also occurs. Patients may suffer from marked psychomotor retardation or agitation and significant weight loss (Rush and Weissenburger, 1994). Maes et al. (1993a) found that the vegetative symptoms of major depression (insomnia and reduced locomotion) were correlated with higher levels of haptoglobulinemia but not with mood state. In one study, serum IL 1-beta, IL-1 receptor antagonist levels were higher in the nonmelancholic MD group than in the melancholic MD group (Kaestner et al., 2005). Rothermundt et al. (2001a) found high levels of leukocyte, lymphocyte, and Natural Killer cell levels in patients with non-melancholic MD and higher IL-2, IL-10 and INF-γ levels in patients with melancholic MD. Marques-Deak et al. (2007) found no difference at IL 1-beta, IL-6, interferon gamma levels among groups according to the type of depression (melancholic–nonmelancholic), process (acute and chronic), severity (heavy and moderate), and course (episodic and recurrent) in 46 untreated female patients with MD. Only a few studies have compared the serum Hp levels in melancholic and nonmelancholic patients. Rothermundt et al. (2001b) showed that there were no differences in serum Hp concentrations among three groups (melancholic MD, non-melancholic MD, and healthy individuals). In two separate studies, Maes et al. (1993b,c) found that in patients with MD, serum Hp levels were higher than in the minor depression and the control group, but there were no differences between the melancholic and nonmelancholic MD groups. In the study
M. Erdem et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 944–947
by Maes et al., the melancholic MD group consisted of 14 and 10 and the nonmelancholic MD group consisted of 29 and 7 patients, respectively. As well as our smaller sample size, the average ages of the patients in the melancholic and nonmelancholic MD groups in our study (35.6 and 34.0, respectively) were lower than ages of both samples of Maes's study (52.6 and 47.1, and 54.8 and 51.7, respectively), which may have caused the results to differ. Factors such as age, sex, diet, circadian rhythm, or the Hp phenotype may affect the serum Hp level (Maes et al., 1993a). Another reason for the differences may be the duration of the disease and the number of depressive episodes. However, neither the duration of disease nor the number of depressive episode has been evaluated in both studies. In previous studies, Celik et al. (2010) and Danner et al. (2003) have shown that cellular and acute-phase response will be affected by number of depressive episode in patients with MD. Some studies have shown that changes in the immune system may be related to the severity of depression in MD patients (Stein et al., 1987, Maes et al., 1991). According to the inflammation hypothesis in MD, the disease is generally associated with a global inflammatory reaction and the severity of the depressive symptoms is positively correlated with inflammation markers (Maes, 1995). Our findings support this hypothesis and the severity of the disease was related to the acute-phase response. An important limitation of our study was the cellular immune response was not evaluated. Another limitation was that previous depressive episodes were not evaluated. Further studies are needed to compare both humoral and cellular immune responses in patients with MD. In conclusion, this study demonstrated that the severity of depression is related to acute-phase responses in patients with melancholic and nonmelancholic MD. Further studies are needed to evaluate other immune response indicators and hypothalamic– pituitary–adrenal axis properties in patients with melancholic and nonmelancholic MD. In the future, it may be interesting and appropriate to investigate changes in indicators of the immune system (e.g. Hp) after treatment by properly designed studies. References Akdemir A, Orsel S, Dag I. Hamilton depresyon derecelendirme olceginin gecerliligi, guvenilirligi ve klinikte kullanimi. 3P Dergisi 1996;4:251–9. Bowman BH. Haptoglobin. In: Bowman BH, editor. Hepatic plasma proteins. San Diego: Academic Press; 1993. p. 159–67. Celik C, Erdem M, Caycı T, Ozdemir B, Ozgur Akgul E, Kurt YG, et al. The association between serum levels of neopterin and number of depressive episodes of major depression. Prog Neuropsychopharmacol Biol Psychiatry 2010;34(2):372–5. Danner M, Kasl SV, Abramson JL, Vaccarino V. Association between depression and elevated C-reactive protein. Psychosom Med 2003;65:347–56. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV axis I disorders (SCID-I), clinical version. Washington D.C: American Psychiatric Press, Inc; 1997. Giblett ER. The haptoglobin system. Ser Haematol 1968;1:3-20.
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