Effect of Selective Serotonin Reuptake Inhibitors and Immunomodulator on Cytokines Levels: An Alternative Therapy for Patients with Major Depressive Disorder
Major depressive disorder (MDD) is a psychiatric illness that presents as a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also experience alterations in cortisol and cytokines levels. Treatment with selective serotonin reuptake inhibitors (SSRIs) is the first-line antidepressant regimen for MDD. The aim of this study was to determine the effect of a combination of SSRIs and an immunomodulator—human dialyzable leukocyte extract (hDLE)—on cortisol and cytokines levels. Patients received SSRIs or SSRIs plus hDLE. The proinflammatory cytokines IL-1β, IL-2, and IFN-γ; anti-inflammatory cytokines IL-13 and IL-10; and 24-h urine cortisol were measured at weeks (W) 0, 5, 20, 36, and 52 of treatment. The reduction in cortisol levels in the SSRI-treated group was 30% until W52, in contrast, the combined treatment induced a 54% decrease at W36. The decline in cortisol in patients who were treated with SSRI plus hDLE correlated with reduction of anti-inflammatory cytokines and increases levels of proinflammatory cytokines at the study conclusion. These results suggest that the immune-stimulating activity of hDLE, in combination with SSRIs, restored the pro- and anti-inflammatory cytokine balance and cortisol levels in depressed patients versus those who were given SSRIs alone. 1. Introduction Clinical and epidemiological studies have established that major depressive disorder (MDD) is a cause of chronic stress [1, 2]. The World Health Organization asserts that MDD will be the second leading cause of incapacity worldwide by 2030 [3], representing a tremendous public health problem with high economic costs [4]. Increased stress levels affect the duration and extent of symptoms of depression [5]. One of the most common clinical features of MDD is the development of hypothalamic-pituitary-adrenal (HPA) axis abnormalities [6, 7]. Chronic hyperactivity of the HPA axis induces hypercortisolism, which affects the nervous, endocrine, and immune systems [8]. The HPA axis function is upregulated by proinflammatory cytokines through the brain receptors for this soluble molecules, expressed mostly at hypothalamus [9]. This stimulation induces a rise on circulatory levels of glucocorticoids that decreases the inflammatory systemic effects induced by cytokines and diminishes the release of CRH at hypothalamus, generating a negative feedback loop. Various studies have linked variations in cytokine and cortisol levels in MDD [10]; one of the first studies of the neuromodulatory effects of cytokines reported the induction of depressive
References
[1]
K. S. Kendler, L. M. Thornton, and C. O. Gardner, “Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis,” American Journal of Psychiatry, vol. 157, no. 8, pp. 1243–1251, 2000.
[2]
R. C. Kessler, P. Berglund, O. Demler et al., “The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R),” The Journal of the American Medical Association, vol. 289, no. 23, pp. 3095–3105, 2003.
[3]
World Health Organization, The Global Burden of Disease 2004 Update, World Health Organization, 2008.
[4]
World Health Organization, “Investing in mental health,” World Health Organization, 2003, http://www.who.int/mental_health/en/.
[5]
S. Moussavi, S. Chatterji, E. Verdes, A. Tandon, V. Patel, and B. Ustun, “Depression, chronic diseases, and decrements in health: results from the World Health Surveys,” The Lancet, vol. 370, no. 9590, pp. 851–858, 2007.
[6]
C. M. Pariante and A. H. Miller, “Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment,” Biological Psychiatry, vol. 49, no. 5, pp. 391–404, 2001.
[7]
F. Holsboer, “The corticosteroid receptor hypothesis of depression,” Neuropsychopharmacology, vol. 23, no. 5, pp. 477–501, 2000.
[8]
M. N. Silverman and E. M. Sternberg, “Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction,” Annals of the New York Academy of Sciences, vol. 1261, pp. 55–63, 2012.
[9]
H. Besedovsky and A. Del Rey, “Brain cytokines as integrators of the immune-neuroendocrine network,” in Handbook of Neurochemistry and Molecular Neurobiology, A. Lajtha, Ed., Springer, 2008.
[10]
P. A. Zunszain, C. Anacker, A. Cattaneo, L. A. Carvalho, and C. M. Pariante, “Glucocorticoids, cytokines and brain abnormalities in depression,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 35, no. 3, pp. 722–729, 2011.
[11]
Z. Kronfol, “Immune dysregulation in major depression: a critical review of existing evidence,” International Journal of Neuropsychopharmacology, vol. 5, no. 4, pp. 333–343, 2002.
[12]
J. C. Felger and F. E. Lotrich, “Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications,” in Neuroscience, vol. 246, pp. 199–229, 2013.
[13]
D. A. Axelson, P. M. Doraiswamy, W. M. McDonald et al., “Hyperocortisolemia and hippocampal changes in depression,” Psychiatry Research, vol. 47, no. 2, pp. 163–173, 1993.
[14]
T. J. Huber, K. Issa, G. Schik, and O. T. Wolf, “The cortisol awakening response is blunted in psychotherapy inpatients suffering from depression,” Psychoneuroendocrinology, vol. 31, no. 7, pp. 900–904, 2006.
[15]
G. Nikisch, A. A. Mathé, A. Czernik et al., “Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response,” Psychopharmacology, vol. 181, no. 4, pp. 751–760, 2005.
[16]
Z. Bhagwagar, R. Whale, and P. J. Cowen, “State and trait abnormalities in serotonin function in major depression,” British Journal of Psychiatry, vol. 180, pp. 24–28, 2002.
[17]
D. J. Kupfer, “Long-term treatment of depression,” Journal of Clinical Psychiatry, vol. 52, supplement 5, pp. 28–34, 1991.
[18]
M. Okuyama-Tamura, M. Mikuni, and I. Kojima, “Modulation of the human glucocorticoid receptor function by antidepressive compounds,” Neuroscience Letters, vol. 342, no. 3, pp. 206–210, 2003.
[19]
C. M. Pariante, A. Makoff, S. Lovestone et al., “Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters,” British Journal of Pharmacology, vol. 134, no. 6, pp. 1335–1343, 2001.
[20]
M. E. Hernández, D. Mendieta, D. Martínez-Fong et al., “Variations in circulating cytokine levels during 52 week course of treatment with SSRI for major depressive disorder,” European Neuropsychopharmacology, vol. 18, no. 12, pp. 917–924, 2008.
[21]
L. Pavon, G. Sandoval-Lopez, M. Eugenia Hernandez et al., “Th2 cytokine response in major depressive disorder patients before treatment,” Journal of Neuroimmunology, vol. 172, pp. 156–165, 2006.
[22]
M. Pompili, P. Venturini, M. Palermo et al., “Mood disorders medications: predictors of nonadherence—review of the current literature,” Expert Review of Neurotherapeutics, vol. 13, no. 7, pp. 809–825, 2013.
[23]
E. Medina-Rivero, G. Merchand-Reyes, L. Pavón et al., “Batch-to-batch reproducibility of transferon,” Journal of Pharmaceutical and Biomedical Analysis, vol. 88, pp. 289–294, 2014.
[24]
J. Byston, K. Cech, J. Pekarek, and J. Jilkova, “Effect of anti-herpes specific transfer factor,” Biotherapy, vol. 9, no. 1–3, pp. 73–75, 1996.
[25]
G. Pizza, C. De Vinci, G. L. Conte et al., “Immunotherapy of metastatic kidney cancer,” International Journal of Cancer, vol. 94, no. 1, pp. 109–120, 2001.
[26]
M. A. Franco-Molina, E. Mendoza-Gamboa, L. Castillo-León, R. S. Tamez-Guerra, and C. Rodríguez-Padilla, “Bovine dialyzable leukocyte extract modulates the nitric oxide and proinflammatory cytokine production in lipopolysaccharide-stimulated murine peritoneal macrophages in vitro,” Journal of Medicinal Food, vol. 8, no. 1, pp. 20–26, 2005.
[27]
R. Berrón-Pérez, R. Chávez-Sánchez, I. Estrada-García et al., “Indications, usage, and dosage of the transfer factor,” Revista Alergia Mexico, vol. 54, no. 4, pp. 134–139, 2007.
[28]
R. M. Sapolsky and P. M. Plotsky, “Hypercortisolism and its possible neural bases,” Biological Psychiatry, vol. 27, no. 9, pp. 937–952, 1990.
[29]
B. S. McEwen, “Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression,” Dialogues in Clinical Neuroscience, vol. 6, no. 2, pp. 119–133, 2004.
[30]
P. M. Plotsky, M. J. Owens, and C. B. Nemeroff, “Psychoneuroendocrinology of depression: hypothalamic-pituitary-adrenal axis,” Psychiatric Clinics of North America, vol. 21, no. 2, pp. 293–307, 1998.
[31]
C. Schüle, T. C. Baghai, D. Eser, M. Schwarz, B. Bondy, and R. Rupprecht, “Effects of mirtazapine on dehydroepiandrosterone-sulfate and cortisol plasma concentrations in depressed patients,” Journal of Psychiatric Research, vol. 43, no. 5, pp. 538–545, 2009.
[32]
R. M？ssner and K.-P. Lesch, “Role of serotonin in the immune system and in neuroimmune interactions,” Brain, Behavior, and Immunity, vol. 12, no. 4, pp. 249–271, 1998.
[33]
L. F？rber, U. Haus, M. Sp？th, and S. Drechsler, “Physiology and pathophysiology of the 5-HT3 receptor,” Scandinavian Journal of Rheumatology, Supplement, vol. 33, no. 119, pp. 2–8, 2004.
[34]
E. M. Sternberg, “Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens,” Nature Reviews Immunology, vol. 6, no. 4, pp. 318–328, 2006.
[35]
P. Blardi, A. De Lalla, A. Leo et al., “Serotonin and fluoxetine levels in plasma and platelets after fluoxetine treatment in depressive patients,” Journal of Clinical Psychopharmacology, vol. 22, no. 2, pp. 131–136, 2002.
[36]
T. Bschor, M. Ising, S. Erbe et al., “Impact of citalopram on the HPA system. A study of the combined DEX/CRH test in 30 unipolar depressed patients,” Journal of Psychiatric Research, vol. 46, no. 1, pp. 111–117, 2012.
[37]
C. M. Pariante, R. B. Kim, A. Makoff, and R. W. Kerwin, “Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membrane steroid transporters,” British Journal of Pharmacology, vol. 139, no. 6, pp. 1111–1118, 2003.
[38]
A. T. Spijker and E. F. C. van Rossum, “Glucocorticoid sensitivity in mood disorders,” Neuroendocrinology, vol. 95, no. 3, pp. 179–186, 2012.
[39]
L. A. Carvalho, M. F. Juruena, A. S. Papadopoulos et al., “Clomipramine in vitro reduces glucocorticoid receptor function in healthy subjects but not in patients with major depression,” Neuropsychopharmacology, vol. 33, no. 13, pp. 3182–3189, 2008.
[40]
V. Contesse, H. Lefebvre, S. Lenglet, J.-M. Kuhn, C. Delarue, and H. Vaudry, “Role of 5-HT in the regulation of the brain-pituitary-adrenal axis: effects of 5-HT on adrenocortical cells,” Canadian Journal of Physiology and Pharmacology, vol. 78, no. 12, pp. 967–983, 2000.
[41]
C. Delarue, V. Contesse, H. Lefebvre et al., “Pharmacological profile of serotonergic receptors in the adrenal gland,” Endocrine Research, vol. 24, no. 3-4, pp. 687–694, 1998.
[42]
D. A. Johnson, E. J. Grant, C. D. Ingram, and S. E. Gartside, “Glucocorticoid receptor antagonists hasten and augment neurochemical responses to a selective serotonin reuptake inhibitor antidepressant,” Biological Psychiatry, vol. 62, no. 11, pp. 1228–1235, 2007.
[43]
D. A. Johnson, C. D. Ingram, E. J. Grant, M. Craighead, and S. E. Gartside, “Glucocorticoid receptor antagonism augments fluoxetine-induced downregulation of the 5-HT transporter,” Neuropsychopharmacology, vol. 34, no. 2, pp. 399–409, 2009.
[44]
J. H. Thakore, C. Barnes, J. Joyce, S. Medbak, and T. G. Dinan, “Effects of antidepressant treatment on corticotropin-induced cortisol responses in patients with melancholic depression,” Psychiatry Research, vol. 73, no. 1-2, pp. 27–32, 1997.
[45]
A. González, F. Fazzino, M. Castillo, S. Mata, and L. Lima, “Serotonin, 5-HT1A serotonin receptors and proliferation of lymphocytes in major depression patients,” NeuroImmunoModulation, vol. 14, no. 1, pp. 8–15, 2007.
[46]
C. Mizrahi, A. Stojanovic, M. Urbina, I. Carreira, and L. Lima, “Differential cAMP levels and serotonin effects in blood peripheral mononuclear cells and lymphocytes from major depression patients,” International Immunopharmacology, vol. 4, no. 8, pp. 1125–1133, 2004.
[47]
G. J. Gormley, M. T. Lowy, A. T. Reder, V. D. Hospelhorn, J. F. Antel, and H. Y. Meltzer, “Glucocorticoid receptors in depression: relationship to the dexamethasone suppression test,” American Journal of Psychiatry, vol. 142, no. 11, pp. 1278–1284, 1985.
[48]
M. T. Lowy, A. T. Reder, G. J. Gormley, and H. Y. Meltzer, “Comparison of in vivo and in vitro glucocorticoid sensitivity in depression: relationship to the dexamethasone suppresion test,” Biological Psychiatry, vol. 24, no. 6, pp. 619–630, 1988.
[49]
L. Lima and M. Urbina, “Serotonin transporter modulation in blood lymphocytes from patients with major depression,” Cellular and Molecular Neurobiology, vol. 22, no. 5-6, pp. 797–804, 2002.
[50]
M. Kubera, M. Maes, G. Kenis, Y.-K. Kim, and W. Lasoń, “Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor α and interleukin-6,” Psychiatry Research, vol. 134, no. 3, pp. 251–258, 2005.
[51]
I. J. Elenkov, “Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being,” Neurochemistry International, vol. 52, no. 1, pp. 40–51, 2008.
[52]
Y. K. Kim, K. S. Na, K. H. Shin, H. Y. Jung, S. H. Choi, and J. B. Kim, “Cytokine imbalance in the pathophysiology of major depressive disorder,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, vol. 31, no. 5, pp. 1044–1053, 2007.
[53]
Y.-K. Kim, S.-W. Lee, S.-H. Kim et al., “Differences in cytokines between non-suicidal patients and suicidal patients in major depression,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, vol. 32, no. 2, pp. 356–361, 2008.
[54]
M. Kubera, G. Kenis, E. Bosmans, S. Scharpé, and M. Maes, “Effects of serotonin and serotonergic agonists and antagonists on the production of interferon-γ and interleukin-10,” Neuropsychopharmacology, vol. 23, no. 1, pp. 89–98, 2000.
[55]
J. Hannestad, N. Dellagioia, and M. Bloch, “The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis,” Neuropsychopharmacology, vol. 36, no. 12, pp. 2452–2459, 2011.
[56]
M. Haack, D. Hinze-Selch, T. Fenzel et al., “Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis,” Journal of Psychiatric Research, vol. 33, no. 5, pp. 407–418, 1999.
[57]
A. Basten, J. D. Pollard, J. G. Stewart, et al., “Transfer factor in treatment of multiple sclerosis,” The Lancet, vol. 2, no. 8201, pp. 931–934, 1980.
[58]
S. Estrada-Parra, A. Nagaya, E. Serrano et al., “Comparative study of transfer factor and acyclovir in the treatment of herpes zoster,” International Journal of Immunopharmacology, vol. 20, no. 10, pp. 521–535, 1998.
[59]
V. Pilotti, M. Mastrorilli, G. Pizza et al., “Transfer factor as an adjuvant to non-small cell lung cancer (NSCLC) therapy,” Biotherapy, vol. 9, no. 1–3, pp. 117–121, 1996.
[60]
S. R. Krutzik, B. Tan, H. Li et al., “TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells,” Nature Medicine, vol. 11, no. 6, pp. 653–660, 2005.
[61]
G. I. Lancaster, Q. Khan, P. Drysdale et al., “The physiological regulation of toll-like receptor expression and function in humans,” Journal of Physiology, vol. 563, no. 3, pp. 945–955, 2005.
