| Abstract|| |
Aims: The aim of the study is to assess and compare serum C-reactive protein (CRP), brain derived neurotrophic factor (BDNF), and interleukin-2 (IL-2) levels in patients with first-episode depression (FED), recurrent depressive disorder (RDD), and healthy controls (HCs) and to determine the relationship between the above-specified inflammatory markers, severity of depression, and stressful life events.
Materials and Methods: Consecutive drug-naive patients with FED and RDD (n = 85) and 50 HCs were studied. Serum concentrations of CRP, brain-derived nerve growth factor (BDNF), and IL-2 were measured. All participants were assessed using Mini-International Neuropsychiatric Interview Plus, Beck's depression inventory, and presumptive stressful life events scale.
Results: The FED and RDD groups had statistically significant lower serum concentration of BDNF and higher IL-2 compared to the HC group, whereas no statistically significant difference was observed with regard to CRP level. No statistically significant differences were observed with regard to the severity of depression and serum concentrations of CRP, BDNF, and IL-2 in the FED and RDD groups. No significant correlation was found between severity of depression and serum concentration of CRP, BDNF, and IL-2 in both the groups. Serum CRP concentration was significantly higher in patients with ≥2 stressful life events. No significant difference was observed between number of stressful life events and BDNF and IL-2 in patients with depression.
Conclusion: FED and RDD are associated with lower serum concentration of BDNF and higher IL-2 compared to the HCs, whereas there appears no difference with regard to CRP level. Multicentric studies are needed to further elucidate the role of inflammatory markers in depression.
Keywords: Brain-derived neurotrophic factor, C-reactive protein, depression, interleukin-2, stress
|How to cite this article:|
Jeenger J, Singroha V, Sharma M, Mathur DM. C-reactive protein, brain-derived neurotrophic factor, interleukin-2, and stressful life events in drug-naive first-episode and recurrent depression: A cross-sectional study. Indian J Psychiatry 2018;60:334-9
|How to cite this URL:|
Jeenger J, Singroha V, Sharma M, Mathur DM. C-reactive protein, brain-derived neurotrophic factor, interleukin-2, and stressful life events in drug-naive first-episode and recurrent depression: A cross-sectional study. Indian J Psychiatry [serial online] 2018 [cited 2021 Oct 15];60:334-9. Available from: https://www.indianjpsychiatry.org/text.asp?2018/60/3/334/243371
| Introduction|| |
Over the last three-to-four decades, research has focused on the relationship between inflammatory markers and psychiatric disorders, especially with regard to etiology, diagnosis, treatment, and prognosis. There is evidence that in patients with depression, inflammatory markers affect the brain functions through changes in neurotransmitter synthesis and metabolism, neuroendocrine functions, and brain structure.,,,,,
Patients with major depressive disorder exhibit all the cardinal features of an inflammatory response, including increased expression of pro-inflammatory cytokines and their receptors and increased levels of acute-phase reactants, chemokines, and soluble adhesion molecules in peripheral blood and cerebrospinal fluid., Interleukin-6 (IL-6) and IL-1 have been most studied in depression. A review of a meta analysis on nine biomarkers of depression reported that IL-6 was most consistently elevated. IL-6 is a pro-inflammatory cytokine that has the ability to cross the blood-brain barrier.
Accumulating evidence suggests low levels of brain-derived neurotrophic factor (BDNF), a candidate molecule involved in the pathophysiology major depression.,, IL-2 has received little research attention with regard to its role in depression. Most researchers have measured the serum soluble IL-2 receptor (sIL-2R) in depressed patients but not serum IL-2 levels. Yang et al. reported a significant increase in sIL-2R which primarily acts as a storage reservoir for circulating IL-2 to increase the longevity of IL-2 signaling but appears not to induce signaling cascades of its own.
In a daily diary study, greater interpersonal stress during a 2-week period was related to higher C-reactive protein (CRP)., This may indicate that not only chronic stress but also acute stress is associated with higher level of circulating markers. There are two possible mechanisms of stress-induced activation of immune responses that involve both sympathetic nervous system and hypothalamic pituitary adrenal (HPA) axis pathways.
A recent systematic review reported that suicidal behavior in depressive patients is specifically associated with elevations of IL-2 and other cytokines. Even a gender difference has been seen, the association between depression and high-sensitivity CRP was much stronger among men than among women. The severity of depression is associated with increased serum CRP level but not in recurrent depressive disorder (RDD). Emotional stressors are linked to RDD and induce an inflammatory response accompanied by increased production of pro-inflammatory cytokines. Patients with major depression have reduced plasma oxygen radical absorbance capacity in comparison to healthy individuals. Consequently, recurrent depressive episodes can contribute to a pro-inflammatory state. These recent studies indicate that the course of depressive disorder may have different immune responses although the evidence so far is inconclusive. It is likely that there may be a difference in inflammatory markers between first-episode depression (FED) and RDD. Given this background, the present researchers primarily aimed to assess and compare serum CRP, BDNF, and IL-2 levels in patients with FED and RDD and healthy controls (HCs). Secondarily, the authors aim to determine the relationship between the inflammatory markers (CRP, BDNF, and IL-2), severity of depression, and stressful life events.
| Materials and Methods|| |
A cross-sectional, observational study was conducted in the Department of Psychiatry, Geetanjali Medical College and Hospital, Udaipur, Rajasthan. The department is part of a multispecialty general hospital rendering tertiary level health services. The study was approved by the Institution Ethics Committee, and informed consent was obtained from all participants of the study. The study was conducted from July 2016 to April 2017.
A total of 85 consecutive patients with depression constituted the study population. The control group (HC) comprised 50 “healthy” individuals without a history of psychiatric and other medical conditions and biologically unrelated to the patients. All participants were screened, including a lifetime evaluation for psychiatric disorders using Mini-International Neuropsychiatric Interview Plus, and diagnoses of depressive disorders were based on the International Classification of Diseases-10., Severity of depression was assessed on Beck's depression inventory. Information on stressful life events was obtained using the presumptive stressful life events (PSLE) scale. All patients were categorized on the basis of number of stressful life events: >2 and ≤2 stressful life events in the last 1 year.
Patients aged 18–65 years and those who provided informed written consent with current depressive episode were included in the study. The study participants were drug naive, i.e., no history of exposed to psychotropic drugs, antibiotics, steroids, structured psychotherapy, electroconvulsive therapy, and any other medications in the last 4 weeks, and they were categorized into two groups – FED and RDD.
Individuals with present and past history of substance use disorders, psychotic disorders, bipolar affective disorder, and depression with psychotic symptoms and anxiety disorders; patients with other medical disorders such as atherosclerotic disease, cerebrovascular event, coronary artery disease, dyslipidemia, acute and chronic inflammatory conditions, diabetes mellitus, and other endocrine-metabolic disorders; patients with a positive urine pregnancy test or postpartum period of <1 year; patients with body mass index (BMI) >24.9 kg/m2 were also excluded from the study.
Evaluation for inflammatory markers
All the patients with depression (FED and RDD) and HCs were assessed after overnight fasting and resting state in the morning. A venous blood sample (5 ml) was drawn and collected in serum separator tube. The samples obtained were allowed to clot for 30 min at room temperature before centrifugation for 15 min at 3000/rpm. Serum was removed immediately in aliquot and stored at ≤−20°C. Repeated freeze–thaw cycles were avoided. Before assaying, the frozen samples were brought to room temperature slowly and mixed gently. The concentration of CRP (mg/dl) was measured using the fully automated biochemistry analyzer COBAS C411 based on electrochemiluminescence. The concentration of BDNF (ng/ml) and IL-2 was measured using the Bio-Rad 680 analyzer based on enzyme-linked immunosorbent assay.,
Statistical analyses were done using the Statistical Package for Social Sciences for Windows, version 16 (SPSS Inc., Chicago, Ill., USA). Continuous covariates were expressed as mean with standard deviation and compared between groups using the unpaired Student's t-test. Discrete covariates were expressed as frequencies compared using Chi-square test. To determine the correlation between variables, Pearson's correlation coefficient was used. All statistical analysis was done at 95% confidence interval and P <0.05 was considered statistically significant.
| Results|| |
The mean age of patients in the FED group and RDD group was 29.11 ± 8.28 and 38.51 ± 9.75 years, respectively [Table 1]. The RDD group comprised more number of patients between the ages of 50–65 years in comparison to the other groups (Χ2 = 15.354, 4 d.f., P = 0.004).
|Table 1: The distribution of individuals according to the age group and gender|
Click here to view
The levels of the inflammatory markers were normally distributed. Patients in the FED and RDD groups had statistically significant lower serum concentration of BDNF and higher IL-2 compared to the HC group, whereas no statistically significant difference was observed with regard to CRP level [Table 2]. No statistically significant differences were observed with regard to the severity of depression and serum concentrations of CRP, BDNF, and IL-2 in patients of the FED and RDD groups [Table 2].
|Table 2: Comparisons of severity of depression and concentrations of C-reactive protein, brain-derived nerve growth factor, and interleukin-2 among patients with first-episode depression, recurrent depressive episodes, and healthy controls|
Click here to view
No significant correlation was found between severity of depressive episode and serum concentration of CRP, BDNF, and IL-2 in the FED and RDD groups [Table 3].
|Table 3: Correlation between severity of depression and serum concentrations of C-reactive protein, brain-derived nerve growth factor, and interleukin-2 in patients with first-episode depression and recurrent depressive disorder|
Click here to view
Serum CRP concentration was significantly higher in patients with two or more stressful life events. No significant difference was observed between number of stressful life events and BDNF and IL-2 in patients with depression [Table 4].
|Table 4: Relationship between number of stressful life events and serum concentrations of C-reactive protein, brain-derived nerve growth factor, and interleukin-2 in patients with depression|
Click here to view
| Discussion|| |
The present study aims to understand the role of biological markers in depression with focus on serum CRP, BDNF, and IL-2 levels in FED, RDD, and HC groups. The pathogenesis of depression has not been fully elucidated, and studies suggest that low-grade systemic inflammation contributes to the development of depression.
According to a systematic review and meta-analysis, the relations of CRP to depression were all cross-sectional and inconsistent. Many researchers have found elevated level of CRP in depressive patients., Matthews et al. found that higher CRP levels led to higher subsequent depressive symptoms, albeit the effect was small. Confounding factors are also play an important role in measuring elevated CRP. However, after adjusting for BMI, there was no significant relationship between CRP and depression. Similarly, in the HUNT population study, CRP levels were raised in those with myocardial infarction (MI) and comorbid MI and depression; the positive association with depression could be explained by confounding factors such as smoking, chronic physical, BMI ≥30 kg/m2, and high coffee consumption. Interaction tests indicated a lower effect of old age and smoking on elevated CRP levels in women compared with men. Previous investigations indicate that obesity is also associated with raised inflammatory markers; hence, individuals with BMI >24.9 kg/m2 were excluded from the study. In contrast to earlier research, we found that serum CRP level among FED and HC groups was positively correlated although weakly (P = 0.697). In the present investigation, RDD and HC groups had positive correlation, but it was statistically nonsignificant (P = 0.060).
BDNF, one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons, synaptic integrity, and synaptic plasticity. We found significantly lower level of serum BDNF in FED and RDD drug-naive patients compared to HCs. Karege et al. were the first to compare serum BDNF levels in depressed subjects with HCs and they found that the BDNF level was significantly lower compared with that in HCs. This decrease was negatively correlated with the severity of depression. Similarly, many researchers reported decreases in serum BDNF level in depressed patients.,,, BDNF levels have been reported to be related to both recurrence and severity of depression. Karege et al. also reported negative correlation in severity of depression and serum BDNF levels. The present study revealed a negative correlation between RDD and serum BDNF. Contrary to earlier reports, we did not observe a statistically significant correlation with severity of depression with serum BDNF level in the FED and RDD groups. BDNF could play an important role in the modulation of neuronal networks and such neuronal plasticity may have an influence on recurrence or recovery of depressive episodes.
There is increasing evidence that major depression is accompanied by an immune response including activation of T-lymphocytes and cells of the monocyte/macrophage lineage. One of the indices of T-cell activation is the increase in sIL-2Rs in the blood of depressed patients and depressed patients who have attempted suicide., The circulating form of the IL-2R p55 subunit, i.e., the sIL-2R, is released from activated T-cells into the blood, and sIL-2R concentrations appear to correlate with T-cell activation and IL-2 secretion in various pathological conditions. The observation that sIL-2R circulating levels are significantly higher in unipolar depressed patients than controls, is consistent with the findings of the present study.
Maes et al. observed that plasma sIL-2R concentrations were elevated in major depression and suggested a coordinated and upregulated production sIL-2R, and other cytokines may constitute a trait marker of major depression. The present investigators also found significantly higher level of serum IL-2 in FED and RDD patients. No relationship was found between severity of depression and serum level of IL-2 in FED and RDD patients in our study. Whereas, Brietzke et al. found positive correlation of mood symptoms with IL-2 and IL-6. The present study estimated serum IL-2 levels in depressed patients unlike previous investigations that have focused on sIL-2R. Whether IL-2 abnormalities are at the level of T-lymphocyte function or IL-2 receptor requires further exploration.
Steptoe et al. suggested a modest increase in circulating inflammatory markers following laboratory-induced psychological stress. Research has demonstrated that psychological distress (and greater frequency of daily interpersonal stress) is associated with higher level of CRP with or without depression.,, In the present study, most of the patients had a history of stressful life events in the last 1 year as assessed on PSLE, and those with two or more stressful life events have higher serum CRP concentration. It may be reasoned that frequent stressful life events or chronic stress associated with HPA overactivity and elevated serum cortisol level may result in the elevation of circulatory inflammatory markers, especially CRP.
In the present study, there were more patients in the age of 50–65 years in the RDD group which may have a bearing on the results. It has been suggested that aging leads to modified/modulated responses of the immune system, influencing the ability to cope with stressors, and not just to an eventually terminal deterioration of the immune system. Testosterone is generally immunosuppressive while estrogen tends to be immunoenhancing. This needs to be borne in mind as there were more males than females in our study. Gender difference in level of inflammatory markers in depression has been reported previously.
The presence of a comparison group, estimation of serum IL-2 levels, inclusion of drug-naive depressed patients, appropriate tools, and exclusion criteria are relative merits of the study. The study is encumbered by certain limitations such as cross-sectional design with small sample size which limits the generalization of the findings. Although the severity and number of depressive episodes were noted, details pertaining to the phenomenological aspects of depression and its relationship with the inflammatory markers were not assessed. There might be a possibility of carrying minor infections by some participants that may have influenced the markers studied and it cannot be ruled out entirely despite our best efforts to exclude those with obvious ailments on the basis of history. No laboratory investigation was carried out to exclude other medical diseases. Future research may include a group with chronic medical illness to allow for stronger comparisons. The categorization of patients with <2 and >2 stressful life events was arbitrary. Clinical sample was drawn from a single tertiary care center, and hence, the findings need replication in other settings for confirmation.
| Conclusion|| |
It is still very early to say that depression is associated with global inflammatory markers. FED and recurrent depression are associated with lower serum concentration of BDNF and higher IL-2 compared to the HCs, whereas there appears no difference with regard to CRP level. There was no significant correlation between the severity of depressive episode and serum concentration of CRP, BDNF, and IL-2. In patients with depression, serum CRP concentration was higher in those with two or more stressful life events. Multicentric studies are needed to further elucidate the role of inflammatory markers in depression.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: Translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012;37:137-62.
Neurauter G, Schröcksnadel K, Scholl-Bürgi S, Sperner-Unterweger B, Schubert C, Ledochowski M, et al.
Chronic immune stimulation correlates with reduced phenylalanine turnover. Curr Drug Metab 2008;9:622-7.
Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol 2002;5:375-88.
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.
Herbert J, Goodyer IM, Grossman AB, Hastings MH, de Kloet ER, Lightman SL, et al.
Do corticosteroids damage the brain? J Neuroendocrinol 2006;18:393-411.
Hamidi M, Drevets WC, Price JL. Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol Psychiatry 2004;55:563-9.
Maes M. Major depression and activation of the inflammatory response system. Adv Exp Med Biol 1999;461:25-46.
Banks WA, Kastin AJ, Gutierrez EG. Penetration of interleukin-6 across the murine blood-brain barrier. Neurosci Lett 1994;179:53-6.
Altar CA. Neurotrophins and depression. Trends Pharmacol Sci 1999;20:59-61.
Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry 1997;54:597-606.
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM, et al.
Neurobiology of depression. Neuron 2002;34:13-25.
Yang ZZ, Grote DM, Ziesmer SC, Manske MK, Witzig TE, Novak AJ, et al.
Soluble IL-2Rα facilitates IL-2-mediated immune responses and predicts reduced survival in follicular B-cell non-Hodgkin lymphoma. Blood 2011;118:2809-20.
Gouin JP, Hantsoo L, Kiecolt-Glaser JK. Immune dysregulation and chronic stress among older adults: A review. Neuroimmunomodulation 2008;15:251-9.
Fuligni AJ, Telzer EH, Bower J, Cole SW, Kiang L, Irwin MR, et al.
Apreliminary study of daily interpersonal stress and C-reactive protein levels among adolescents from Latin American and European backgrounds. Psychosom Med 2009;71:329-33.
Serafini G, Pompili M, Elena Seretti M, Stefani H, Palermo M, Coryell W, et al.
The role of inflammatory cytokines in suicidal behavior: A systematic review. Eur Neuropsychopharmacol 2013;23:1672-86.
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.
Jeenger J, Sharma M, Mathur DM, Amandeep. Associations of number and severity of depressive episodes with C-reactive protein and interleukin-6. Asian J Psychiatr 2017;27:71-5.
Talarowska M, Bobińska K, Zajączkowska M, Su KP, Maes M, Gałecki P, et al.
Impact of oxidative/nitrosative stress and inflammation on cognitive functions in patients with recurrent depressive disorders. Med Sci Monit 2014;20:110-5.
Behr GA, Moreira JC, Frey BN. Preclinical and clinical evidence of antioxidant effects of antidepressant agents: Implications for the pathophysiology of major depressive disorder. Oxid Med Cell Longev 2012;2012:609421.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al.
The mini-international neuropsychiatric interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59 Suppl 20:22-33.
Amorim P. Mini International Neuropsychiatric Interview (MINI): Validation of a short structured diagnostic psychiatric interview. Rev Bras Psiquiatr 2000;22:106-15.
Ajmany S, Nandi DN. Adaptation of AT. Beck et al
.'s an inventory for measuring depression. Indian J Psychiatry 1973;15:391.
Singh G, Kaur D, Kaur H. Presumptive stressful life events scale (psles) – A new stressful life events scale for use in India. Indian J Psychiatry 1984;26:107-14.
] [Full text]
de Beer FC, Hind CR, Fox KM, Allan RM, Maseri A, Pepys MB, et al.
Measurement of serum C-reactive protein concentration in myocardial ischaemia and infarction. Br Heart J 1982;47:239-43.
Kuo HK, Yen CJ, Chang CH, Kuo CK, Chen JH, Sorond F, et al.
Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population: Systematic review and meta-analysis. Lancet Neurol 2005;4:371-80.
Liukkonen T, Silvennoinen-Kassinen S, Jokelainen J, Räsänen P, Leinonen M, Meyer-Rochow VB, et al.
The association between C-reactive protein levels and depression: Results from the Northern Finland 1966 birth cohort study. Biol Psychiatry 2006;60:825-30.
Elovainio M, Aalto AM, Kivimäki M, Pirkola S, Sundvall J, Lönnqvist J, et al.
Depression and C-reactive protein: Population-based health 2000 study. Psychosom Med 2009;71:423-30.
Matthews KA, Schott LL, Bromberger JT, Cyranowski JM, Everson-Rose SA, Sowers M, et al.
Are there bi-directional associations between depressive symptoms and C-reactive protein in mid-life women? Brain Behav Immun 2010;24:96-101.
Douglas KM, Taylor AJ, O'Malley PG. Relationship between depression and C-reactive protein in a screening population. Psychosom Med 2004;66:679-83.
Bjerkeset O, Romild U, Smith GD, Hveem K. The associations of high levels of C-reactive protein with depression and myocardial infarction in 9258 women and men from the HUNT population study. Psychol Med 2011;41:345-52.
Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999;282:2131-5.
Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM, et al.
Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 2002;109:143-8.
Lee BH, Kim H, Park SH, Kim YK. Decreased plasma BDNF level in depressive patients. J Affect Disord 2007;101:239-44.
Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, et al.
Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 2003;54:70-5.
Piccinni A, Marazziti D, Catena M, Domenici L, Del Debbio A, Bianchi C, et al.
Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments. J Affect Disord 2008;105:279-83.
Dell'Osso L, Del Debbio A, Veltri A, Bianchi C, Roncaglia I, Carlini M, et al.
Associations between brain-derived neurotrophic factor plasma levels and severity of the illness, recurrence and symptoms in depressed patients. Neuropsychobiology 2010;62:207-12.
Thapar A, McGuffin P. Anxiety and depressive symptoms in childhood – A genetic study of comorbidity. J Child Psychol Psychiatry 1997;38:651-6.
Maes M, Meltzer HY, Buckley P, Bosmans E. Plasma-soluble interleukin-2 and transferrin receptor in schizophrenia and major depression. Eur Arch Psychiatry Clin Neurosci 1995;244:325-9.
Nunes SO, Reiche EM, Morimoto HK, Matsuo T, Itano EN, Xavier EC, et al.
Immune and hormonal activity in adults suffering from depression. Braz J Med Biol Res 2002;35:581-7.
Nässberger L, Träskman-Bendz L. Increased soluble interleukin-2 receptor concentrations in suicide attempters. Acta Psychiatr Scand 1993;88:48-52.
Caruso C, Candore G, Cigna D, Colucci AT, Modica MA. Biological significance of soluble IL-2 receptor. Mediators Inflamm 1993;2:3-21.
Maes M, Bosmans E, Suy E, Vandervorst C, De Jonckheere C, Raus J, et al.
Immune disturbances during major depression: Upregulated expression of interleukin-2 receptors. Neuropsychobiology 1990;24:115-20.
Maes M, Meltzer HY, Bosmans E, Bergmans R, Vandoolaeghe E, Ranjan R, et al.
Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 1995;34:301-9.
Maes M, Meltzer HY, Buckley P, Bosmans E. Plasma-soluble interleukin-2 and transferrin receptor in schizophrenia and major depression. Eur Arch Psychiatry Clin Neurosci 1995;244:325-9.
Brietzke E, Stertz L, Fernandes BS, Kauer-Sant'anna M, Mascarenhas M, Escosteguy Vargas A, et al.
Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord 2009;116:214-7.
Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun 2007;21:901-12.
Steptoe A. Psychophysiological contributions to behavioral medicine and psychosomatics. Handbook of Psychophysiology. Cambridge: Cambridge University Press; 2007. p. 723-51.
Puustinen PJ, Koponen H, Kautiainen H, Mäntyselkä P, Vanhala M. Psychological distress and C-reactive protein: Do health behaviours and pathophysiological factors modify the association? Eur Arch Psychiatry Clin Neurosci 2011;261:277-84.
Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, et al.
Immunosenescence and inflamm-aging as two sides of the same coin: Friends or foes? Front Immunol 2017;8:1960.
Roved J, Westerdahl H, Hasselquist D. Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences. Horm Behav 2017;88:95-105.
Dr. Manu Sharma
Department of Psychiatry, Geetanjali Medical College and Hospital, Udaipur - 313 002, Rajasthan
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4]