|Year : 2014 | Volume
| Issue : 2 | Page : 74-77
A study of changes in inflammatory markers in patients of depression
Deepti Jangpangi1, Sunita Mondal1, Rajiv Bandhu1, Dinesh Kataria2, Jayashree Bhattacharjee3, Asha Gandhi1
1 Department of Physiology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
2 Department of Psychiatry, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
3 Department of Biochemistry, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
|Date of Web Publication||20-Mar-2015|
C 2/11, Flat No-3, First Floor, IGNOU Road, Saidula-Jab Ext, New Delhi - 110 030
Source of Support: None, Conflict of Interest: None
Background: Depression may result in unfavorable health outcomes as it has been associated with cardiovascular morbidity. Recent researches have suggested the role of inflammation in the pathophysiology of depression and co-morbidities associated with it although the underlying mechanism relating the two is still unclear. Aim: The present study aimed to explore the association between depression and inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and high sensitive c-reactive protein (hsCRP). Materials and Methods: Thirty drug-naοve patients of depression diagnosed on the basis of ICD-10 criteria, in the age group of 20-45 years were included in the study. They were compared with 30 age, gender, body mass index, socio-economic and educational status matched apparently healthy controls. The blood samples were taken after an overnight fast and serum samples were immediately stored until the time of analysis. Results: The serum levels of hsCRP were significantly higher (P = 0.042) in depression group as compared to the control group. Although the mean serum levels of IL-6 and TNF-α were higher in patients of depression, they were not statistically significant (IL-6: P = 0.055, TNF-α: P = 0.053). Conclusion: It can be inferred from our study that depression is associated with underlying low-grade inflammation, which might contribute to increased morbidity in patients of depression.
Keywords: Depression, high sensitive c-reactive protein, interleukin-6, tumor necrosis factor-alpha
|How to cite this article:|
Jangpangi D, Mondal S, Bandhu R, Kataria D, Bhattacharjee J, Gandhi A. A study of changes in inflammatory markers in patients of depression. J Mental Health Hum Behav 2014;19:74-7
|How to cite this URL:|
Jangpangi D, Mondal S, Bandhu R, Kataria D, Bhattacharjee J, Gandhi A. A study of changes in inflammatory markers in patients of depression. J Mental Health Hum Behav [serial online] 2014 [cited 2019 Aug 21];19:74-7. Available from: http://www.jmhhb.org/text.asp?2014/19/2/74/153714
| Introduction|| |
Depression is a disorder of major public health concern not only in terms of decreased quality of life but also due to the considerable morbidity and economic burden associated with it  and has been listed as third leading cause of global disease burden.  Recent researches suggest that activation of an inflammatory response system may play an etiological role in depression. , It has been supported by several studies that have found elevated levels of pro-inflammatory cytokines in patients of depression.  The cytokines such as interleukin-6 (IL-6) along with tumor necrosis factor-alpha (TNF-α) plays a role in the regulation of cellular immunity, and inflammatory response, and these are produced both peripherally and in central nervous system. , IL-6 also results in activation of acute phase response in liver, leading to the production of acute phase proteins c-reactive protein (CRP).  Sustained increases in systemic levels of these inflammatory mediators have also been shown to increase the risk of various diseases like cardiovascular disease, stroke, diabetes and mortality. ,, A significant positive association has also been reported between depression and increased levels of IL-6, TNF-α and CRP in patients of depression relative to controls. ,,
Though the above studies have found a positive association between inflammation and depression, several other studies have revealed conflicting, and inconclusive results,  and some studies reported inverse association between the two. 
Thus, the present study was attempted in Indian population diagnosed with depression without any co-morbid diseases and prior to initiation of therapy and aims to study changes in inflammatory markers in them.
| Materials and Methods|| |
The study was approved by the Institutional Ethics Committee. The study was carried out in the Department of Physiology and Department of Psychiatry in association with Department of Biochemistry, Lady Hardinge Medical College (LHMC), New Delhi. The duration of the study was from November 2010 to March 2012. The study recruited 30 drug-naïve patients in the age group of 20-45 years and compared with age and gender-matched healthy controls. The diagnosis was confirmed independently by a psychiatrist using International Classification of Diseases (ICD-10) (ICD-10 Classifications of Mental and Behavioral Disorders).  Patients suffering from any known physical illnesses or any other psychiatric disorders, and those with substance dependence, pregnant and lactating females as assessed by history, clinical examination were excluded from the study.
Control group was consisted of 30 age, gender, body mass index and socio-economic status matched healthy volunteers. Controls were randomly selected attendants of patients, which were not blood related, utilizing the other out-patient services of LHMC, New Delhi. They were chosen after excluding those with any known physical disorders, psychiatric disorders, those with substance abuse, pregnant or lactating females were also excluded. The objective and study design was explained to all the patients and controls, and their informed written consent was taken. A semi-structured proforma was filled with socio-demographic details. As per ICD-10, out of 30 depression patients, 8 were suffering from mild depression, 16 were suffering from moderate depression, and 6 from severe depression.
Body mass index (Kg/m 2 ) was computed as body weight in kilograms divided by the square of standing height in meters.  Blood Pressure (Systolic blood pressure [SBP]/Diastolic blood pressure [DBP]) was measured by auscultation as per American heart association guidelines. 
After an overnight fast, blood samples for the assays were collected between 9.00 am and 12 noon to obviate any diurnal variations, from patients of depression and healthy volunteers. In depression patients, the blood samples were taken along with other necessary routine investigations advised by Psychiatrist. Three milliliter of blood samples collected in tubes with no additives were centrifuged to isolate the serum. Serum samples obtained were immediately stored in aliquots at −70°C until the time of analysis for the measurement of IL-6, TNF-α and high sensitive CRP (hsCRP) levels. Inflammatory markers were assayed using enzyme linked immuno-sorbent assay (ELISA) in Department of Biochemistry, LHMC, New Delhi. This is a solid phase sandwich ELISA for the in-vitro qualitative and quantitative determination of inflammatory markers in serum samples. The instrument used as ELISA reader was URIT-660 Microplate reader, model no 660, manufactured by URIT Medical Electronic Co., Ltd, China.
Interleukin-6 and TNF-α serum levels were estimated using the human ELISA kit supplied by DIACLONE research (France). The sensitivity of Diaclone IL-6 ELISA kit was <2 pg/ml, while that of Diaclone TNF-α ELISA kit was <8 pg/ml.
High sensitive C-reactive protein serum levels were estimated using hsCRP ELISA kit supplied by CALBIOTECH Inc, USA. The sensitivity of the hsCRP kit was 10 ng/ml.
All parameters were expressed as mean ± standard error of the mean. The various parameters of parametric data of depression patients were compared with age and gender matched healthy controls using unpaired Students t-test. Nonparametric data of inflammatory markers in depression patients were compared with controls using Mann-Whitney U-test. Chi-square test was employed to compare discrete variables. All the statistical evaluations were done using a GraphPad Prism Software version 5 (GraphPad Software Inc., San Diego, CA, USA).
| Results|| |
[Table 1] shows the comparison of socio-demographic parameters between the depression patients and controls. No significant difference was found in between the two groups, except of height which was significantly more in the control group compared to patient group.
|Table 1: Demographic parameters between depression patients and normal controls (mean±SEM)|
Click here to view
[Table 2] illustrates the physiological and biochemical parameters results between the patients of depression and normal controls. No significant difference was observed in SBP and DBP in between the two groups. The serum levels of inflammatory markers IL-6, TNF-α, hsCRP were higher in depression group compared to the control group; however, the statistical significance could be found only in case of hsCRP. (IL-6: P = 0.055, TNF-α: P = 0.053, hsCRP: P = 0.042).
|Table 2: Comparison of physiological parameters and inflammatory markers of depression patients and normal controls (mean±SEM)|
Click here to view
| Discussion|| |
Our study demonstrates that hsCRP levels were significantly higher in depression group relative to controls. The inflammatory cytokines IL-6 and TNF-α were higher in patients of depression as compared to the control group though not statistically significant. This could be interpreted as depression is associated with underlying low-grade inflammation as CRP is consider as a marker of systemic inflammation and a potential biomarker of immunological activation. , Our study is in concordance with several cross-sectional population-based studies that have reported a positive association between CRP and depression. , Pasco et al. also showed hsCRP is an independent risk marker for de novo major depressive disorder in women.  Although Ford et al. found significant increased levels of CRP only in men but not in women. 
It remains unclear whether depression is causing inflammatory pathways activation or some other processes (such as stress) induced inflammation precedes to the depressive symptoms.  Psychological stress, which is a common risk factor for the depression might provide a link between depression and inflammation.  Several studies have indicated that psychological stress activates proinflammatory cytokines and their signaling pathways in brain and periphery.  Recent evidences also suggest that prolonged activation of inflammatory pathways in the brain may result in decreased neurotrophic support, oxidative stress leading to excitotoxicity and dysregulation of cognitive functions that characterize depressive disorders. ,
Although most of the studies have found an association between depression and inflammation, other studies have not consistently obtained the same results.  Thus, it can be said that pathophysiology of depression is uncertain and is probably varied and complex, inflammation may play a subtle role or may act as a risk factor ultimately leading to depression in vulnerable individuals.  The strength of our study is that we examined inflammatory markers in clinically diagnosed depressive patients prior to initiation of therapy. We also excluded subjects with other psychiatric and physical co-morbidities that could potentially confound the results. However, there are some limitations in our study, one is small sample size which might was not sufficient to detect a significant association between depression and serum levels of IL-6 and TNF-α. The sample size is very small to draw any conclusion. The cross-sectional nature of study limits us to draw any inference about the direction of the association. Longitudinal studies are required to investigate whether inflammation precede the depression or followed by depression or whether there is a bidirectional relationship. 
There is a current need to study neurobiological pathways and mediators related to depression to develop more comprehensive treatment programs in the future for depressive patients and to detect morbidities associated with it.  Identification of possible biomarkers related to depression not only will help in aiding the diagnosis but will also help in developing new drugs targeting them.
| References|| |
Wells KB, Stewart A, Hays RD, Burnam MA, Rogers W, Daniels M, et al.
The functioning and well-being of depressed patients. Results from the Medical Outcomes Study. JAMA 1989;262:914-9.
Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS, et al.
Grand challenges in global mental health. Nature 2011;475:27-30.
Belmaker RH, Agam G. Major depressive disorder. N Engl J Med 2008;358:55-68.
Penninx BW, Milaneschi Y, Lamers F, Vogelzangs N. Understanding the somatic consequences of depression: Biological mechanisms and the role of depression symptom profile. BMC Med 2013;11:129.
Krishnadas R, Cavanagh J. Depression: An inflammatory illness? J Neurol Neurosurg Psychiatry 2012;83:495-502.
Murphy K, Travers P, Walport M. Janeway's Immunobiology. 7 th
ed. New York: Garland Science; 2008.
Steinke JW, Borish L. 3. Cytokines and chemokines. J Allergy Clin Immunol 2006;117 2 Suppl Mini-Primer: S441-5.
Miller AH, Raison CL. Immune system contributes to the pathophysiology of depression. FOCUS 2008;6:36-45.
Nicholson A, Kuper H, Hemingway H. Depression as an aetiologic and prognostic factor in coronary heart disease: A meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur Heart J 2006;27:2763-74.
Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan: A meta-analysis. Diabetes Care 2008;31:2383-90.
Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, et al.
C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: An individual participant meta-analysis. Lancet 2010;375:132-40.
Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis. Psychosom Med 2009;71:171-86.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al.
A meta-analysis of cytokines in major depression. Biol Psychiatry 2010;67:446-57.
Liu Y, Ho RC, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-a) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: A meta-analysis and meta-regression. J Affect Disord 2012;139:230-9.
Kagaya A, Kugaya A, Takebayashi M, Fukue-Saeki M, Saeki T, Yamawaki S, et al.
Plasma concentrations of interleukin-1beta, interleukin-6, soluble interleukin-2 receptor and tumor necrosis factor alpha of depressed patients in Japan. Neuropsychobiology 2001;43:59-62.
Whooley MA, Caska CM, Hendrickson BE, Rourke MA, Ho J, Ali S. Depression and inflammation in patients with coronary heart disease: Findings from the Heart and Soul Study. Biol Psychiatry 2007;62:314-20.
World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization; 1992.
National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Bethesda (MD): National Heart, Lung, and Blood Institute; 1998.
Perloff D, Grim C, Flack J, Frohlich ED, Hill M, McDonald M, et al.
Human blood pressure determination by sphygmomanometry. Circulation 1993;88 (5 Pt 1):2460-70.
Pepys MB, Hirschfield GM. C-reactive protein: A critical update. J Clin Invest 2003;111:1805-12.
De Berardis D, Campanella D, Gambi F, La Rovere R, Carano A, Conti CM, et al.
The role of C-reactive protein in mood disorders. Int J Immunopathol Pharmacol 2006;19:721-5.
Pikhart H, Hubacek JA, Kubinova R, Nicholson A, Peasey A, Capkova N, et al.
Depressive symptoms and levels of C-reactive protein: A population-based study. Soc Psychiatry Psychiatr Epidemiol 2009;44:217-22.
Panagiotakos DB, Pitsavos C, Chrysohoou C, Tsetsekou E, Papageorgiou C, Christodoulou G, et al.
Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA study. Eur Heart J 2004;25:492-9.
Pasco JA, Nicholson GC, Williams LJ, Jacka FN, Henry MJ, Kotowicz MA, et al.
Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry 2010;197:372-7.
Ford DE, Erlinger TP. Depression and C-reactive protein in US adults: Data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 2004;164:1010-4.
Berk M, Williams LJ, Jacka FN, O'Neil A, Pasco JA, Moylan S, et al.
So depression is an inflammatory disease, but where does the inflammation come from? BMC Med 2013;11:200.
Raison CL, Capuron L, Miller AH. Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends Immunol 2006;27:24-31.
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009;65:732-41.
Makhija K, Karunakaran S. The role of inflammatory cytokines on the aetiopathogenesis of depression. Aust N Z J Psychiatry 2013;47:828-39.
Stewart JC, Rand KL, Muldoon MF, Kamarck TW. A prospective evaluation of the directionality of the depression-inflammation relationship. Brain Behav Immun 2009;23:936-44.
[Table 1], [Table 2]