|Year : 2018 | Volume
| Issue : 1 | Page : 42-47
Tumor necrosis factor receptor in Egyptian patients with bipolar disorder during mania: a case–controlled study
Aref A Khoweiled1, Osama R Ibrahim1, Nagwan M Madbouly1, Walaa A Rabie2, Noha A Mahfouz1
1 Department of Psychiatry, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||09-Oct-2017|
|Date of Acceptance||07-Nov-2017|
|Date of Web Publication||29-Jan-2018|
Noha A Mahfouz
Department of Psychiatry, Faculty of Medicine, Cairo University, Egypt, 12 Nile Corniche Street, Maadi, Cairo 11956
Source of Support: None, Conflict of Interest: None
Background The role of inflammation has received increasing attention as a potential pathophysiological mechanism in bipolar disorder (BD).
Objective To compare the level of soluble tumor necrosis factor-α receptor 1 (sTNFR1) in manic state of BD with healthy controls and investigate the relation between its level and the severity of BD.
Patients and methods Serum levels of sTNFR1 were measured with enzyme-linked immunosorbent assay techniques in 44 patients with BD-I during the manic episode and 88 healthy controls recruited from Kasr Al Ainy Hospital, Cairo University. The severity of the manic symptoms was assessed using Young Mania Rating Scale.
Results The level of sTNFR1 was higher in patients with BD-I, with the most recent episode manic, than in healthy control. Patients with BD-I, with the most recent episode manic, with psychotic features had higher levels of sTNFR1 than those without psychotic features. sTNFR1 level correlated with Young Mania Rating Scale scores.
Conclusion High level of sTNFR1 may be considered as state marker in manic episodes in patients with BD-I. The more severe the disease, the higher the level of sTNFR1.
Keywords: bipolar disorder, inflammation, manic, tumor necrosis factor
|How to cite this article:|
Khoweiled AA, Ibrahim OR, Madbouly NM, Rabie WA, Mahfouz NA. Tumor necrosis factor receptor in Egyptian patients with bipolar disorder during mania: a case–controlled study. Egypt J Psychiatr 2018;39:42-7
|How to cite this URL:|
Khoweiled AA, Ibrahim OR, Madbouly NM, Rabie WA, Mahfouz NA. Tumor necrosis factor receptor in Egyptian patients with bipolar disorder during mania: a case–controlled study. Egypt J Psychiatr [serial online] 2018 [cited 2018 Nov 16];39:42-7. Available from: http://new.ejpsy.eg.net/text.asp?2018/39/1/42/224009
| Introduction|| |
Bipolar disorder (BD) is among the most debilitating and severe mental illnesses. The precise neurobiology underlying BD is still unclear (Leboyer et al., 2012). Immune abnormalities play a major role in both the pathophysiology and the treatment of BD (Brietzke et al., 2011). In BD, immune disturbances are related to symptom severity (Goldstein et al., 2009), mood episodes (Brietzke et al., 2009), neurotrophin alterations (Brietzke et al., 2012), metabolic disturbances (Tsai et al., 2012), effect of medications (Guloksuz et al., 2012), and comorbidity of allergic and autoimmune disorders (Jerrell et al., 2010).
Previous studies found that inflammatory biomarkers are implicated in the pathophysiology of BD, and these are related to acute illness episodes (Kapczinski et al., 2011).
Several cytokines and cytokine receptors are elevated in BD in the manic phase (Munkholm et al., 2013a, 2013b). Tumor necrosis factor-α (TNF-α) acts by binding two receptors (Vandenabeele et al., 1995). The soluble forms of the tumor necrosis factor-α receptors (sTNFR1 and sTNFR2) modulate the activity of TNF-α (Diez-Ruiz et al., 1995). Specially, soluble TNF-α receptors appear to prolong the half-life of TNF-α by influencing neuroprotective effects and by protecting it against proteolytic degradation (Granell et al., 2004).
When TNF-α binds to TNFR1, it leads to nuclear factor-κ activation and recruitment of associated death domain protein-mediated apoptosis (Chen and Goeddel, 2002). TNFR2 has a major role in suppressing inflammatory responses mediated by TNF (Carpentier et al., 2004). Because sTNFR1 and sTNFR2 may be more stable than TNF-α, some authors suggest that these soluble receptors are more valid markers of TNF-α activity and, accordingly, of inflammatory activity (Kronfol and Remick, 2000).
Several studies have evaluated TNF-α and suggested that it represents a potential biomarker for BD. Kapczinski et al. (2009) showed that higher levels of TNF-α may indicate advanced stages of BD. Kim et al. (2007) found that patients in a manic state have significantly higher levels of TNF-α than individuals without BD. Moreover, Barbosa et al. (2013) found that patients with BD during the manic phase showed increased circulating levels of TNF-α and sTNFR.
The aim of this work is to (a) compare the level of sTNFR1 in patients with manic state of BD with healthy controls and (b) assess the correlation between the elevation of serum level of sTNFR1 and the severity of the disease. It is hypothesized that (a) serum levels of sTNFR1 will be elevated in patients with mania compared with healthy controls, and (b) there will be a positive correlation between serum levels of sTNFR1 and the severity of the current manic episode of BD.
| Patients and methods|| |
The protocol of the study was approved by the Scientific and the Ethical Committees of the Department of Psychiatry, Faculty of Medicine, Cairo University. A written informed consent was obtained from all subjects participating in the study with explanation of the purpose of the study ensuring them of the confidentiality of the information that participation was totally voluntary and that it did not imply a direct benefit for the participant. Decision to exit from the study at any time without giving any justification was accepted and did not affect the treatment plan. Any detected psychopathology was referred for treatment and follow-up.
This is a case–control study in which 44 patients with BD during mania were recruited from Kasr Al Ainy Psychiatry Hospital and 88 healthy volunteer controls from paramedical workers in other departments of the same hospital. The patients fulfilled the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) (American Psychiatric Association, 2013) for BD (manic episode). All patients were kept on their regular regimen of psychotropic medications. Patients who were on any other nonpsychiatric medications and/or had received electroconvulsive therapy (ECT) within the past 6 months were excluded. Subjects with history or current organic brain disease, medical illness, and substance abuse disorder were also excluded from all groups. This was to exclude factors that could alter sTNFR1 levels.
The interviews and sample collection were done over 9 months from May 2014 to February 2015. The interview ranged from one and a half to two hours. Patients fulfilling the inclusion criteria were first interviewed using the Kasr Al Ainy psychiatric interview. Diagnosis was confirmed by the Structured Clinical Interview for DSM-IV Axis I disorder (SCID-I) (Ventura et al., 1998). The diagnosis was compared and matched to the DSM-5 criteria and written accordingly. Patients with bipolar I disorder, manic phase, were subjected to the Young Mania Rating Scale (YMRS) (Young et al., 1978) to assess the severity of the manic symptoms. As for the healthy controls, the SCID-I was done to rule out any psychiatric illness. The height and weight were measured for all participants to calculate the BMI. Then, a venous sample was drawn from them, during the period between 9:00 a.m. and 11:00 a.m., in a serum separator tube for the sTNFR1 assessment. Within 30 min of collection, the sample was delivered and centrifuged for 15 min. Serum was extracted and stored at −80°C. Serum sTNFR1 concentrations were measured by enzyme-linked immunoassay (ELISA) (Van Weemen and Schuurs, 1971) (Quantikine ELISA, cat. no. DRT100, SRT100, PDRT100; R&D systems, Minnesota, USA).
Data were analyzed using statistical package for the social sciences, version 22 (SPSS Inc. Chicago, Illinois, USA). Nominal data were summarized as number (n) and frequencies (percentages). Associations between nominal data were investigated using χ2 and Fisher’s exact tests. Data were tested for normality using Kolmogorov–Smirnov test. Numerical data were represented as mean and SD. Differences between groups were detected using Student’s t-test. Pearson’s correlation coefficient was used for linear relations between quantitative variables (Chan, 2003). P value of less than 0.05 was considered statistically significant.
| Results|| |
Demographics and clinical data
Participants were matched for age (P=0.130) and sex (P=0.712). Patients did not differ from controls in education (P=0.351), residency (P=0.388), BMI (P=0.266), and cigarette smoking (P=0.900) ([Table 1]).
The onset of the current illness in patients with bipolar I disorder, with most recent episode manic, ranged between 0.2 and 5 months, with a mean of 1.6±1.4 months. Overall, 65.9% (n=29) of these patients had psychotic features (according to SCID-I). The clinical data for patient group are shown in [Table 2].
Most of the patients with current manic episode (43.2%) had moderate severity of symptoms on YMRS, and 18.2% of them had severe illness or remission of some of their symptoms ([Figure 1]).
|Figure 1 Symptom severity by YMRS for patients with bipolar I disorder, currently manic. YMRS, Young Mania Rating Scale.|
Click here to view
Serum levels of soluble tumor necrosis factor receptor 1
There was a statistically significant difference between the two groups regarding the mean level of sTNFR1 where patients with manic states had higher levels than controls ([Table 3]).
|Table 3 Mean level of soluble tumor necrosis factor receptor 1 in patients and controls|
Click here to view
Soluble tumor necrosis factor receptor 1 and psychotic features
Patients with bipolar I disorder, with the most recent episode manic, with psychotic features (n=29) had statistically significant higher mean levels of sTNFR1 (1540.96±262.18 pg/ml) than those without psychotic features (1174.67±171.55 pg/ml, P<0.001).
Soluble tumor necrosis factor receptor 1 and Young Mania Rating Scale
There was a significant positive correlation between level of sTNFR1 and severity of manic episode in patients with bipolar I disorder, with the most recent episode manic, assessed by YMRS (r=0.814, P<0.001), that is, as the manic episode was more severe, the higher was the level of sTNFR1 ([Figure 2]).
|Figure 2 Correlation between level of sTNFR1 (pg/ml) and severity of manic episode in patients with bipolar I disorder, most recent episode manic. sTNFR1, soluble tumor necrosis factor receptor 1; YMRS, Young Mania Rating Scale.|
Click here to view
Soluble tumor necrosis factor receptor 1 and other variables
There was no association between the level of sTNFR1 and BMI (r=−0.84, P=0.588) nor cigarette smoking (P=0.141) in patients with bipolar I disorder, with the most recent episode manic.
| Discussion|| |
This study showed that the serum level of sTNFR1 was higher in patients with bipolar I disorder, currently manic, compared with the control group. Furthermore, the more the severity of the manic episode, the higher the level of sTNFR1. In addition, patients with bipolar I disorder, currently manic, with psychotic features had higher levels of sTNFR1 than those without psychotic features. Increased TNF-α and sTNFR1 levels in patients with BD indicate the presence of a proinflammatory state. Because sTNFR1 is more stable than TNF-α, it is a more reliable marker of proinflammatory states (Barbosa et al., 2011).
The pivotal point in this study was the mean level of sTNFR1 in the manic phase of the illness compared with healthy controls. Elevated levels of the proinflammatory cytokine, TNF-α (O’Brien et al., 2006; Kim et al., 2007; Ortiz-Domínguez et al., 2007), as compared with healthy controls, were reported during manic episodes, suggesting that mania might be a proinflammatory state. Increased TNF-α levels in patients with BD might represent hypothalamic–pituitary–adrenal axis dysfunction or steroid resistance of immune cells (Knijff et al., 2006). It was also suggested that TNF-α could possibly be a state marker in the disease, reflecting overall disease activity (Munkholm et al., 2013a, 2013b). TNF-α activates an apoptotic signaling cascade leading to cell death and acts through other signaling networks affecting neuronal development, cell survival, and synaptic transmission (Park and Bowers, 2010). Moreover, some researchers claim that TNF-α might be a trait marker because of its steady high levels after the treatment of acute episode (Brietzke and Kapczinski, 2008; Soczynska et al., 2009).
It is worth noting here that we had excluded any subject who had received ECT in the past 6 months (before withdrawal of the blood sample) to avoid ECT administration as a confounding variable that might affect the results. Guloksuz et al. (2014) suggested that a single session of ECT induces an acute transient immune activation, whereas repetitive ECT treatment results in long-term down-regulation of immune activation.
The finding that patients with bipolar I disorder, recent episode manic, with psychotic features had higher levels of sTNFR1 than those without psychotic features goes in line with several studies and meta-analyses that have found evidence of increased levels of TNF-α in BD (Dowlati et al., 2010; Drexhage et al., 2010), and a previous study also reported that TNF-α was correlated with positive psychotic symptoms (Erbaægci et al., 2001). Research regarding the relationship between immune factors and disorder characteristics in psychotic patient populations is sparse (Miller et al., 2011). To add further solidarity to our results, a recent study demonstrated that TNFR1 was the only inflammatory marker that was both highly significantly elevated compared with controls, as well as related to several clinical severity measures. This supports that TNFR1 is a key inflammatory marker in severe mental disorders. Based on raised serum levels of TNF in a previous meta-analysis, Hope et al. (2013) examined if activities in this pathway were associated with severity of the mental disorders. The main finding was a significant association between clinical severity and levels of sTNFR1 in BD with psychotic features.
| Limitations|| |
The use of medications could potentially be a limitation, as mood stabilizers have a predominantly anti-inflammatory action. However, all blood samples of patients during the manic phase were collected within 1 week of initiation of the mood stabilizer, as before the onset of their current episode, they were not adherent to medications. We thought that its anti-inflammatory action − if present − would be minimal by that time.
| Recommendations|| |
Considering sTNFR1 as a biomarker of mood state in clinical practice may help in early intervention and prevention efforts and may help to monitor the response to various treatments. In addition, new adjunctive drug treatment strategies (adding of anti-inflammatory medications) could be developed for combined treatments with either existing or newly developed medications. This would lead to individualization of treatment approaches and to investigation of the use of anti-inflammatory medications in BD, thereby increasing the chances of positive therapeutic outcomes.
| Conclusion|| |
The level of sTNFR1 was higher in patients with bipolar I disorder, currently manic, compared with the control group. The more the severity of the manic episode, the higher the level of sTNFR1. Patients with psychotic features had higher levels of sTNFR1 than those without psychotic features. Thus, high level of sTNFR1 might be considered as state marker in manic episodes in patients with BD.
Authors sincerely thank all participants who actively shared in this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing.
Barbosa IG, Huguet RB, Mendonça VA, Sousa LP, Neves FS, Bauer ME et al.
(2011). Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder. Eur Arch Psychiatry Clin Neurosci 261:139–143.
Barbosa IG, Rocha NP, Bauer ME, de Miranda AS, Huguet RB, Reis HJ et al.
(2013). Chemokines in bipolar disorder: trait or state?. Eur Arch Psychiatry Clin Neurosci 263:159–165.
Brietzke E, Kapczinski F (2008). TNF-α as a molecular target in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 32:1355–1361.
Brietzke E, Stertz L, Fernandes BS, Kauer-Sant’anna M, Mascarenhas M, Escosteguy Vargas A et al.
(2009). Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord 116:214–217.
Brietzke E, Stabellini R, Grassis-Oliveira R, Lafer B (2011). Cytokines in bipolar disorder: Recent findings, deleterious effects but promise for future therapeutics. CNS Spectr 16:157–168.
Brietzke E, Mansur RB, Soczynska JK, Kapczinski F, Bressan RA, McIntyre RS (2012). Towards a multifactorial approach for prediction of bipolar disorder in at risk populations. J Affect Disord 140:82–91.
Carpentier I, Coornaert B, Beyaert R (2004). Function and regulation of tumor necrosis factor type 2. Curr Med Chem 11:2205–2212.
Chan YH (2003). Biostatistics 104: correlational analysis. Singapore Med J 44:614–619.
Chen G, Goeddel DV (2002). TNF-R1 signaling: a beautiful pathway. Science 296:1634–1635.
Diez-Ruiz A, Tilz GP, Zangerle R, Baier-Bitterlich G, Wachter H, Fuchs D (1995). Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis. Eur J Haematol 54:1–8.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK et al.
(2010). A meta-analysis of cytokines in major depression. Biol Psychiatry; 67:446–457.
Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA et al.
(2010). The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert Rev Neurother 10:59–76.
Erbaægci AB, Herken H, Köylüoglu O, Yilmaz N, Tarakçioglu M (2001). Serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment. Mediators Inflamm 10:109–115.
Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS (2009). Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry 70:1078–1090.
Granell S, Pereda J, Gómez-Cambronero L, Cassinello N, Sabater L, Closa D et al.
(2004). Circulating TNF-alpha and its soluble receptors during experimental acute pancreatitis. Cytokine 25:187–191.
Guloksuz S, Altinbas K, Aktas C, Kenis G, Bilgic Gazioglu S, Deniz G et al.
(2012). Evidence for an association between tumor necrosis factor-alpha levels and lithium response. J Affect Disord 143:148–152.
Guloksuz S, Rutten B, Arts B, van Os J, Kenis G (2014). The immune system and electroconvulsive therapy for depression. J ECT 30:132–137.
Hope S, Ueland T, Steen NE, Dieset I, Lorentzen S, Berg AO et al.
(2013). Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder. Schizophr Res 145:36–42.
Jerrell JM, McIntyre RS, Tripathi A (2010). A cohort study of the prevalence and impact of comorbid medical conditions in pediatric bipolar disorder. J Clin Psychiatry 71:1518–1525.
Kapczinski F, Fernandes B, Kauer-Sant’Anna M, Gama C, Yatham L, Berk M (2009). The concept of staging in bipolar disorder: the role of BDNF and TNF-alpha as biomarkers. Acta Neuropsychiatr 21:272–274.
Kapczinski F, Dal-Pizzol F, Teixeira AL, Magalhaes PV, Kauer-Sant’ Anna M, Klamt F et al.
(2011). Peripheral biomarkers and illness activity in bipolar disorder. J Psychiatr Res 45:156–161.
Kim Y, Jung H, Myint A, Kim H, Park S (2007). Imbalance between proinflammatory cytokines in bipolar disorder. J Affect Disord 104:91–95.
Knijff EM, Breunis MN, van Geest MC, Kupka RW, Ruwhof C, de Wit HJ et al.
(2006). A relative resistance of T cells to dexamethasone in bipolar disorder. Bipolar Disord 8:740–750.
Kronfol Z, Remick DG (2000). Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 157:683–694.
Leboyer M, Soreca I, Scott J, Frye M, Henry C, Tamouza R et al.
(2012). Can bipolar disorder be viewed as a multi-system inflammatory disease?. J Affect Disord 141:1–10.
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B (2011). Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 70:663–671.
Munkholm K, Braüner JV, Kessing LV, Vinberg M (2013a). Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatr Res 47:1119–1133.
Munkholm K, Vinberg M, Kessing L (2013b). Cytokines in bipolar disorder: a systematic review and meta-analysis. J Affect Disord 144:16–27.
O’Brien SM, Scully P, Scott LV, Dinan TG (2006). Cytokine profiles in bipolar affective disorder: Focus on acutely ill patients. J Affect Disord 90: 263–267.
Ortiz-Domínguez A, Hernández ME, Berlang aC, Gutiérrez-Mora D, Moreno J, Heinze G et al.
(2007). Immune variations in bipolar disorder: phasic differences. Bipolar Disord 9:596–602.
Park KM, Bowers WJ (2010). Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 22:977–983.
Soczynska JK, Kennedy SH, Goldstein BI, Lachowski A, Woldeyohannes HO, McIntyre RS (2009). The effect of tumor necrosis factor antagonists on mood and mental health-associated quality of life: novel hypothesis-driven treatments for bipolar depression?. Neurotoxicology 30:497–521.
Tsai SY, Chung KH, Wu JY, Kuo CJ, Lee HC, Huang SH (2012). Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder. J Affect Disord 136:110–116.
Van Weemen BK, Schuurs AH (1971). Immunoassay using antigen-enzyme conjugates. FEBS Lett 15:232–236.
Vandenabeele P, Declercq W, Beyaert R, Fiers W (1995). Two tumour necrosis factor receptors: structure and function. Trends Cell Biol 5:392–399.
Ventura J, Liberman RP, Green MF, Shaner A, Mintz J (1998). Training and quality assurance with the Structured Clinical Interview for DSM-IV (SCID-I/P). Psychiatry Res 79:163–173.
Young RC, Biggs JT, Ziegler VE, Meyer DA (1978). A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429–435.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]