The relationship between serum levels of haptoglobin and neopterin and the number of episodes in patients with major depression

Abstract

Objective: In explaining the association between depression and immune system pro-inflammatory cytokines have come to the fore and there appears to be an increase in particular at the cellular immune response. Neopterin measurements enable monitoring of the cellular immune response although its specific function is still not fully described. Similarly, haptoglobin (Hp), a positive acute phase protein, has been mentioned as well. In this study, we aimed to investigate the effects of depressive episodes on serum levels of neopterin and Hp by comparing serum haptoglobin and neopterin levels of the depressive patients in their first attack with those of depression patients suffering from recurrent attacks, and with the healthy control group. Method: Eighty patients who admitted to the outpatient psychiatry clinic of Ankara Gulhane Military Medical Academy (GMMF) were included in the study. Fourty-four individuals were being followed up with a diagnosis of first episode depression. There were 36 patients in the recurrent major depression (MD) group. The control group consisted of 41 healthy individuals. Of recurrent MD patients, 22 patients were in their second episode, 16 patients were in their third attack and 6 patients had four episodes or more. Severity of depression was evaluated with 17-item Hamilton Depression Rating Scale (HAM-D). Peripheral venous blood samples were collected from participants to determine complete blood count, routine biochemistry, serum neopterin, and haptoglobin measurements. The levels of serum neopterin and haptoglobin were measured by using the samples that were collected between the hours of 8:00 am and 11:00 am after 12 hour fasting during the previous night. Results: There was no significant difference between the three groups in terms of gender, age, educational level, and smoking. There was also not significant difference between the first episode MD and recurrent MD groups for HAM-D scores. No significance was detected between the first episode MD and control groups in terms of serum Hp and neopterin levels. In the recurrent MD group serum Hp and neopterin levels were higher than those of the first episode MD patients and the control subjects. HAM-D scores of MD patients (both first-episode MD and recurrent MD group) were correlated with serum levels of Hp, but there was no correlation between serum neopterin levels and HAM-D scores. Conclusion: The independent factor affecting the neopterin and Hp levels in patients with MD was found as the number of episodes of depression. Recurrent episodes have resulted with increased levels of both markers. We believe that this finding is important. Our findings support the hypothesis that major depressive disorder is generally associated with widespread inflammatory reaction and severity of depressive symptoms are positively correlated with the increase in inflammatory markers. Serum levels of Hp were associated with depression severity in patients who had a single episode as well as patients with multiple episodes. The same relationship was not found for neopterin. Further studies are needed to determine the importance of this difference observed between the two markers and also etiological significance of them.

Keywords

• depression, neopterin, haptoglobins

Majör Depresyon Hastalarında Atak Sayısı ile Serum Haptoglobulin ve Neopterin Düzeyleri Arasındaki İlişki

Öz

Amaç: Depresyon ile immün sistem arasındaki ilişkinin açıklanmasında pro–inflamatuar sitokinler ön plana çıkmakta ve özellikle hücresel immün yanıtta artma görülmektedir. Halen özgül işlevi tam olarak bilinmeyen neopterin ölçümleri hücresel immün yanıtının izlenmesini sağlar. Aynı şekilde pozitif bir akut faz proteini olan haptoglobulin (Hp) üzerinde de durulmaktadır. Bu çalışmada ilk atağında olan depresyon hastaları ile tekrarlayan ataklar geçiren depresyon hastalarının serum neopterin ve haptoglobulin seviyelerinin sağlıklı kontrol grubu ve birbirleri ile karşılaştırılması yoluyla depresif atakların neopterin ve Hp düzeyleri üzerine etkilerinin araştırılması amaçlanmıştır. Yöntem: Çalışmaya Ankara Gülhane Askeri Tıp Akademisi (GATA) Psikiyatri polikliniğine başvuran 80 hasta alındı. 44 hasta ilk atak depresyon tanısı ile takip edilmekteydi. Tekrarlayan ataklar geçiren grupta ise 36 hasta vardı. Sağlıklı kontrol grubu ise 41 kişiden oluşuyordu. Tekrarlayan majör depresyon (MD) grubunda 22 hasta ikinci, 16 hasta üçüncü atağında, 6 hasta ise dört ya da daha fazla atak geçirmiş durumdaydı. Depresyon şiddeti 17 maddelik Hamilton Depresyon Ölçeği (HDÖ) ile değerlendirildi. Tam kan, rutin biyokimya, serum neopterin ve haptoglobulin düzeylerinin saptanması için katılımcılardan periferik venöz kan örnekleri alındı. Serum neopterin and haptoglobin düzeyleri katılımcılar gece boyunca 12 saat aç kaldıktan sonra sabah 8:00 ve 11:00 saatleri arasında ölçüldü. Bulgular: Yaş, eğitim düzeyi, sigara kullanımı ve cinsiyet açısından her üç grup arasında anlamlı bir farklılık yoktu. İlk atak MD ve tekrarlayan MD grupları arasında da HDÖ skorları açısından anlamlı bir farklılık yoktu. İlk atak MD grubu ile kontrol grubu arasında serum Hp ve neopterin açısından fark saptanmadı. Tekrarlayan MD grubunda serum Hp ve neopterin seviyesi ilk atak MD grubuna ve kontrol grubuna göre yüksek bulundu. MD hastalarının (hem ilk atak MD hem de tekrarlayan MD grubunda) HDÖ skorları ile serum Hp seviyeleri arasında ilişki vardı, ancak HDÖ skorları ile serum neopterin seviyeleri arasında herhangi bir ilişki yoktu. Sonuç: MD hastalarının neopterin ve Hp seviyelerini etkileyen bağımsız etken depresyon atak sayısı olarak bulundu. Tekrarlayan ataklar ilk atak hastalarından farklı olarak her iki belirtecin düzeylerinin artması ile sonuçlanmıştır. Bu bulgunun önemli olduğunu düşünüyoruz. Bulgularımız MD’de hastalığın genellikle yaygın inflamatuvar reaksiyon ile ilişkili olduğu ve depresif belirtilerin şiddetinin inflamatuvar belirteçler ile pozitif bir şekilde ilişkili olduğu hipotezini desteklemektedir. Hem tek atak geçiren hem de birden fazla atak geçiren hastaların serum Hp seviyeleri depresyonun ciddiyeti ile ilişkili bulunmuştur. Aynı ilişki neopterin için bulunamamıştır. Her iki belirteç arasında gözlenen bu farklılığın öneminin saptanması ve bu belirteçlerin etyolojik öneminin kesin olarak saptanması için ileri çalışmalara gereksinim vardır.

Anahtar Kelimeler

• depresyon, neopterin, haptoglobinler

References

1. Kenis G, Maes M. Effects of antidepressants on the production of cytokines. Int J Neuropsychopharmacol. 2002;5:401-12.
2. Sluzewska A, Rybakowski J, Bosmans E, Sobieska M, Berghmans R, Maes M, Wiktorowicz K. Indicators of immune activation in major depression. Psychiatry Res. 1996;64:161-7.
3. Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R. The new ‘5-HT’ hypothesis of depression: Cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;5:702-21.
4. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24-31.
5. Hoffmann G, Wirleitner B, Fuchs D. Potential role of immun system activation associated production of neopterin derivatives in humans. Inflamm Res. 2003;52:313-21.
6. Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D. Neopterin production, tryptophan degradation, and mental depression--what is the link? Brain Behav Immun. 2002;16:590-5.
7. Çelik C, Erdem M, Özdemir B, Çaycı T, Türker T, Özgen F. Treatment of major depression with sertraline: Relationship between serum neopterin levels and respond to the treatment. Bulletin of Clinical Psychopharmacology. 2010;20:134-9.
8. Landmann R, Schaub B, Link S, Wacker HR. Unaltered monocyte function in patients with major depression before and after three months of antidepressive therapy. Biol Psychiatry. 1997;41:675-81.

9. O’Toole SM, Chiappelli F, Rubin RT. Plasma neopterin in major depression: relationship to basal and stimulated pituitary-adrenal cortical axis function. Psychiatry Res. 1998;79:21-9.
10. Hoekstra R, van den Broek WW, Fekkes D, Bruijn JA, Mulder PG, Pepplinkhuizen L. Effect of electroconvulsive therapy on biopterin and large neutral amino acids in severe, medication-resistant depression. Psychiatry Res. 2001;103:115-23.
11. Kohl C, Walch T, Huber R, Kemmler G, Neurauter G, Fuchs D, Solder E, Schrocksnadel H, Sperner-Unterweger B. Measurement of tryptophan, kynurenine and neopterin in women with and without postpartum blues. J Affect Disord. 2005;86:135-42.
12. Maes M, Scharpe S, Meltzer HY, Okayli G, Bosmans E, D’Hondt P, Vanden Bossche BV, Cosyns P. Increased neopterin and interferongamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatry Res. 1994;54:143-60.
13. Matsuda J, Gohchi K, Gotoh N. Serum concentrations of 2’,5’oligoadenylate synthetase, neopterin, and beta-glucan in patients with chronic fatigue syndrome and in patients with major depression. J Neurol Neurosurg Psychiatry. 1994;57:1015-21.
14. Hoekstra R, Fekkes D, van de Wetering BJ, Pepplinkhuizen L, Verhoeven WM. Effect of light therapy on biopterin, neopterin and tryptophan in patients with seasonal affective disorder. Psychiatry Res. 2003;120:37-42.
15. Celik C, Erdem M, Caycı T, Ozdemir B, Akgül EÖ, Kurt YG, Yaman H, Isıntaş M, Ozgen F, Ozsahin A. The association between serum levels of neopterin and number of depressive episodes of major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2010;34:372-5.
16. Bowman BH. Haptoglobin. In: Bowman BH, editors. Hepatic plasma proteins. San Diego: Academic Press;1993:159-67.
17. Maes M, Scharpe S, Bosmans E, Vandewoude M, Suy E, Uyttenbroeck W, Cooreman W, Vandervorst, Raus J. Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that ilness. Prog Neuropsychopharmacol Biol Psychiatry. 1992;16:501-15.
18. 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.
19. 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. 1994;151:112-16.
20. Erdem M, Çelik C, Çaycı T, Özdemir B, Kurt YG, Akgül EÖ, Yaman H, Balıkcı A, Uzun Ö. Serum haptoglobin levels in patients with melancholic and nonmelancholic major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2011;35:944-7.
21. Maes M, Scharpe S, Cosyns P, Meltzer H. Relationships between basal hypothalamic-pituitary-adrenal axis activity and plasma haptoglobin levels in depression. J Psychiatr Res. 1994;28:123-34.
22. Hurwitz EL, Morgenstern H. Cross-sectional associations of asthma, hay fever and other allergies with major depression and low back pain among adults aged 20–39. Am J Epidemiol. 1999;150:1107-16.
23. Ongur D, Katz IR, Meyers BS, Schneider LS, Lebowitz BD. Glia reduction in subgenual pre frontal cortex in mood disorders. Proc Natl Acad Sci USA. 1998;95:13290-5.
24. Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY. Morphometric evidence for neuronal and glia prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45:1085-98.
25. Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metabolic brain disease. 2009;24:27-53.
26. Aydemir O, Deveci A, Taskin OE, Taneli F, Danaci-Esen A. Serum brain-derived neurotrophic factor level in dysthymia: A comparative study with major depressive disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2007;31:1023-6.
27. Rodrigo Grassi-Oliveira, Moises Evandro Bauer, Julio Carlos Pezzi, Antonio Lucio Teixeira, Elisa Brietzke. Interleukin-6 and verbal memory in recurrent major depressive disorder. Activitas Nervosa Superior Rediviva. 2011;53:134-8.
28. Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain behavior and immunity. 2001;25:181-213.
29. Nibuya M, Takahashi M, Russell DS, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroshock seizures in rat hippocampus. Neurosci Lett. 1999;267:81-4.
30. Maes M, Twisk FN, Ringel K. Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression. Psychother Psychosom. 2012;81:286-95.
31. Tiemeier H, Fekkes D, Hofman A, Van Tuijl HR, Kiliaan AJ, Breteler MM. Plasma pterins and folate in late life depression: the Rotterdam Study. Psychiatry Res. 2006;145:199-206.
32. Maes M, Ringel K, Kubera M, Berk M, Rybakowski J. Increased autoimmune activity against 5-HT: a key component of depression that is associated with inflammation and activation of cellmediated immunity, and with severity and staging of depression. J Affect Disord. 2012;136:386-92.
33. Maes M, Mihaylova I, Kubera M, Ringel K. Activation of cellmediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2012;36:169-75.
34. 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. 1993;47:229-41.
35. Maes M, Scharpe S, Meltzer HY, Bosmans E, Suy E, Calabrese J, Cosyns P. Relationships between interleukin-6 activity, acute phase proteins and function of the hypothalamic–pituitary– adrenal axis in severe depression. Psychiatry Res. 1993;49:11–27.
36. Maes M, Scharpe S, Meltzer HY, Cosyns P. Relationships between increased haptoglobin plasma levels and activation of cellmediated immunity in depression. Biol Psychiatry. 1993;34:69070
37. Danner M, Kasl SV, Abramson JL, Vaccarino V. Association between depression and elevated C-reactive protein. Psychosom Med. 2003;65:347-56.
38. Rothermundt M, Arolt V, Fenker J, Gutbrodt H, Peters M, Kirchner H. Different immune patterns in melancholic and nonmelancholic major depression. Eur Arch Psychiatry Clin Neurosci. 2001;251:90-7.
39. Stein M, Schleifer SJ, Keller SE. Psychoimmunology in clinical psychiatry. Psychiatric update: The American psychiatric association annual review 1987.
40. Maes M, Bosman E, Suy E, Minner B, Raus J. A further exploration of the relationships between immune parameters and the HPAaxis activity in depressed patients. Psychol Med. 1991;21:313-20.
41. Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 1995;19:11-38.