There is a substantial unmet need for biomarkers to predict treatment response in major depressive disorder (MDD). Evidence has converged on activation of the inflammatory response system as a fundamental mechanism underlying MDD.
By investigating circulating leukocyte subsets quantified by fluorescence-activated cell sorting (FACS) analysis before treatment, we aim to predict antidepressant response.
Forty medication-free inpatients with melancholic, non-psychotic depression before treatment with either venlafaxine or imipramine and 40 age- and gender-matched healthy controls were included. Leukocyte subsets were quantified by FACS analysis using frozen peripheral blood mononuclear cells (PBMC) collected prior to and after 7 weeks of treatment with either venlafaxine (375 mg/day) or imipramine (blood level 200–300 ng/ml). Response was defined as at least 50 % reduction of the baseline Hamilton Rating Scale for Depression (HAM-D) score.
Prior to treatment, MDD patients showed reduced percentages of CD4+CD25highFoxp3+ T regulatory (Treg) cells when compared with controls (1.5 ± 0.6 vs. 1.8 ± 0.6, p = .037). After treatment, robust rises in Treg cells were observed in patients (1.8 ± 0.7, p < .001), yet Treg cells were not predictors of the clinical outcome of treatment. Antidepressant non-responders showed increased CD8+ cytotoxic T cell percentages (24.0 ± 8.6 vs. 15.9 ± 5.9, p = .004) and decreased natural killer (NK) cell percentages (14.0 ± 6.9 vs. 21.4 ± 11.9, p = .020) compared with responders before treatment. Both lymphocyte levels were not significantly modulated by treatment.
In melancholic MDD, FACS analysis of circulating leukocyte subpopulations might help to discriminate between patients with high or low responsiveness to antidepressant treatment.
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American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders, 4th, text rev. edn, Washington, DC
Amital D, Fostick L, Silberman A, Beckman M, Spivak B (2008) Serious life events among resistant and non-resistant MDD patients. J Affect Disord 110:260–4
Basterzi AD, Yazici K, Buturak V, Cimen B, Yazici A, Eskandari G, Tot Acar S, Tasdelen B (2010) Effects of venlafaxine and fluoxetine on lymphocyte subsets in patients with major depressive disorder: a flow cytometric analysis. Prog Neuro-Psychopharmacol Biol Psychiatry 34:70–5
Baumeister D, Russell A, Pariante CM, Mondelli V (2014) Inflammatory biomarker profiles of mental disorders and their relation to clinical, social and lifestyle factors. Soc Psychiatry Psychiatr Epidemiol 49:841–9
Benedetti F, Lucca A, Brambilla F, Colombo C, Smeraldi E (2002) Interleukine-6 serum levels correlate with response to antidepressant sleep deprivation and sleep phase advance. Prog Neuro-Psychopharmacol Biol Psychiatry 26:1167–70
Benedetti F, Dallaspezia S, Lorenzi C, Pirovano A, Radaelli D, Locatelli C, Poletti S, Colombo C, Smeraldi E (2012) Gene-gene interaction of glycogen synthase kinase 3-beta and serotonin transporter on human antidepressant response to sleep deprivation. J Affect Disord 136:514–9
Binder EB, Owens MJ, Liu W, Deveau TC, Rush AJ, Trivedi MH, Fava M, Bradley B, Ressler KJ, Nemeroff CB (2010) Association of polymorphisms in genes regulating the corticotropin-releasing factor system with antidepressant treatment response. Arch Gen Psychiatry 67:369–79
Blume J, Douglas SD, Evans DL (2011) Immune suppression and immune activation in depression. Brain Behav Immun 25:221–9
Brouwer JP, Appelhof BC, van Rossum EF, Koper JW, Fliers E, Huyser J, Schene AH, Tijssen JG, Van Dyck R, Lamberts SW, Wiersinga WM, Hoogendijk WJ (2006) Prediction of treatment response by HPA-axis and glucocorticoid receptor polymorphisms in major depression. Psychoneuroendocrinology 31:1154–63
Carbone F, De Rosa V, Carrieri PB, Montella S, Bruzzese D, Porcellini A, Procaccini C, La Cava A, Matarese G (2014) Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nat Med 20:69–74
Carvalho LA, Bergink V, Sumaski L, Wijkhuijs J, Hoogendijk WJ, Birkenhager TK, Drexhage HA (2014) Inflammatory activation is associated with a reduced glucocorticoid receptor alpha/beta expression ratio in monocytes of inpatients with melancholic major depressive disorder. Transl Psychiatry 4:e344
Chen Y, Jiang T, Chen P, Ouyang J, Xu G, Zeng Z, Sun Y (2011) Emerging tendency towards autoimmune process in major depressive patients: a novel insight from Th17 cells. Psychiatry Res 188:224–30
Cook IA, Hunter AM, Gilmer WS, Iosifescu DV, Zisook S, Burgoyne KS, Howland RH, Trivedi MH, Jain R, Greenwald S, Leuchter AF (2013) Quantitative electroencephalogram biomarkers for predicting likelihood and speed of achieving sustained remission in major depression: a report from the biomarkers for rapid identification of treatment effectiveness in major depression (BRITE-MD) trial. JClin Psychiatry 74:51–6
Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67:446–57
Evans DL, Ten Have TR, Douglas SD, Gettes DR, Morrison M, Chiappini MS, Brinker-Spence P, Job C, Mercer DE, Wang YL, Cruess D, Dube B, Dalen EA, Brown T, Bauer R, Petitto JM (2002) Association of depression with viral load, CD8 T lymphocytes, and natural killer cells in women with HIV infection. Am J Psychiatry 159:1752–9
Eyre H, Baune BT (2012) Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology 37:1397–416
Farid Hosseini R, Jabbari Azad F, Talaee A, Miri S, Mokhber N, Farid Hosseini F, Esmaeili H, Mahmoudi M, Rafatpanah H, Mohammadi M (2007) Assessment of the immune system activity in Iranian patients with Major Depression Disorder (MDD). Iran J Immunol : IJI 4:38–43
Fava M, Rush AJ, Alpert JE, Balasubramani GK, Wisniewski SR, Carmin CN, Biggs MM, Zisook S, Leuchter A, Howland R, Warden D, Trivedi MH (2008) Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry 165:342–51
First MB, Spitzer RL, Gibbon M, Williams JBW (1999) Structured clinical interview for DSM-IV axis I disorders. Dutch translation. . Swets & Zeitlinger
Flentge F, van den Berg MD, Bouhuys AL, The HT (2000) Increase of NK-T cells in aged depressed patients not treated with antidepressive drugs. Biol Psychiatry 48:1024–7
Frank MG, Hendricks SE, Burke WJ, Johnson DR (2004) Clinical response augments NK cell activity independent of treatment modality: a randomized double-blind placebo controlled antidepressant trial. Psychol Med 34:491–8
Freier E, Weber CS, Nowottne U, Horn C, Bartels K, Meyer S, Hildebrandt Y, Luetkens T, Cao Y, Pabst C, Muzzulini J, Schnee B, Brunner-Weinzierl MC, Marangolo M, Bokemeyer C, Deter HC, Atanackovic D (2010) Decrease of CD4(+)FOXP3(+) T regulatory cells in the peripheral blood of human subjects undergoing a mental stressor. Psychoneuroendocrinology 35:663–73
Frick LR, Rapanelli M, Cremaschi GA, Genaro AM (2009) Fluoxetine directly counteracts the adverse effects of chronic stress on T cell immunity by compensatory and specific mechanisms. Brain Behav Immun 23:36–40
Furey ML, Drevets WC, Hoffman EM, Frankel E, Speer AM, Zarate CA Jr (2013) Potential of pretreatment neural activity in the visual cortex during emotional processing to predict treatment response to scopolamine in major depressive disorder. JAMA Psychiatry 70:280–90
Gold SM, Kruger S, Ziegler KJ, Krieger T, Schulz KH, Otte C, Heesen C (2011) Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression. J Neurol Neurosurg Psychiatry 82:814–8
Grosse L, Carvalho LA, Wijkhuijs AJ, Bellingrath S, Ruland T, Ambree O, Alferink J, Ehring T, Drexhage HA, Arolt V (2015) Clinical characteristics of inflammation-associated depression: monocyte gene expression is age-related in major depressive disorder. Brain Behav Immun 44:48–56
Guereschi MG, Araujo LP, Maricato JT, Takenaka MC, Nascimento VM, Vivanco BC, Reis VO, Keller AC, Brum PC, Basso AS (2013) Beta2-adrenergic receptor signaling in CD4+ Foxp3+ regulatory T cells enhances their suppressive function in a PKA-dependent manner. Eur J Immunol 43:1001–12
Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62
Hepgul N, Cattaneo A, Zunszain PA, Pariante CM (2013) Depression pathogenesis and treatment: what can we learn from blood mRNA expression? BMC Med 11:28
Hernandez ME, Martinez-Fong D, Perez-Tapia M, Estrada-Garcia I, Estrada-Parra S, Pavon L (2010) Evaluation of the effect of selective serotonin-reuptake inhibitors on lymphocyte subsets in patients with a major depressive disorder. Eur Neuropsychopharmacol : J Eur Coll Neuropsychopharmacol 20:88–95
Himmerich H, Milenovic S, Fulda S, Plumakers B, Sheldrick AJ, Michel TM, Kircher T, Rink L (2010) Regulatory T cells increased while IL-1beta decreased during antidepressant therapy. J Psychiatr Res 44:1052–7
Hunter AM, Leuchter AF, Power RA, Muthen B, McGrath PJ, Lewis CM, Cook IA, Garriock HA, McGuffin P, Uher R, Hamilton SP (2013) A genome-wide association study of a sustained pattern of antidepressant response. J Psychiatr Res 47:1157–65
Knijff EM, Ruwhof C, de Wit HJ, Kupka RW, Vonk R, Akkerhuis GW, Nolen WA, Drexhage HA (2006) Monocyte-derived dendritic cells in bipolar disorder. Biol Psychiatry 59:317–26
Ko FY, Tsai SJ, Yang AC, Zhou Y, Xu LM (2013) Association of CD8 T cells with depression and anxiety in patients with liver cirrhosis. Int J Psychiatry Med 45:15–29
Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H (2000) Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacol: Off Pub Am Coll Neuropsychopharmacol 22:370–9
Li Y, Xiao B, Qiu W, Yang L, Hu B, Tian X, Yang H (2010) Altered expression of CD4(+)CD25(+) regulatory T cells and its 5-HT(1a) receptor in patients with major depression disorder. J Affect Disord 124:68–75
Mahnke K, Ring S, Bedke T, Karakhanova S, Enk AH (2008) Interaction of regulatory T cells with antigen-presenting cells in health and disease. Chem Immunol Allergy 94:29–39
McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF, Sorant AJ, Papanicolaou GJ, Laje G, Fava M, Trivedi MH, Wisniewski SR, Manji H (2006) Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 78:804–14
Miller AH (2010) Depression and immunity: a role for T cells? Brain Behav Immun 24:1–8
Miller AH, Maletic V, Raison CL (2009) Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65:732–41
Muller N (2014) Immunology of major depression. Neuroimmunomodulation 21:123–30
Nijhuis LE, Olivier BJ, Dhawan S, Hilbers FW, Boon L, Wolkers MC, Samsom JN, de Jonge WJ (2014) Adrenergic beta2 receptor activation stimulates anti-inflammatory properties of dendritic cells in vitro. PLoS One 9:e85086
Pacheco R, Riquelme E, Kalergis AM (2010) Emerging evidence for the role of neurotransmitters in the modulation of T cell responses to cognate ligands. Cent Nerv Syst Agents Med Chem 10:65–83
Pariante CM, Miller AH (1995) Natural killer cell activity in major depression: a prospective study of the in vivo effects of desmethylimipramine treatment. Eur Neuropsychopharmacol : J Eur Coll Neuropsychopharmacol 5(Suppl):83–8
Raison CL, Miller AH (2013) Role of inflammation in depression: implications for phenomenology, pathophysiology and treatment. Mod Trends Pharmacopsychiatr 28:33–48
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70:31–41
Ravindran AV, Griffiths J, Merali Z, Anisman H (1995) Lymphocyte subsets associated with major depression and dysthymia: modification by antidepressant treatment. Psychosom Med 57:555–63
Ravindran AV, Griffiths J, Merali Z, Anisman H (1998) Circulating lymphocyte subsets in major depression and dysthymia with typical or atypical features. Psychosom Med 60:283–9
Samson AC, Meisenzahl E, Scheuerecker J, Rose E, Schoepf V, Wiesmann M, Frodl T (2011) Brain activation predicts treatment improvement in patients with major depressive disorder. J Psychiatr Res 45:1214–22
Schlatter J, Ortuno F, Cervera-Enguix S (2004) Lymphocyte subsets and lymphokine production in patients with melancholic versus nonmelancholic depression. Psychiatry Res 128:259–65
Schmidt D, Reber SO, Botteron C, Barth T, Peterlik D, Uschold N, Mannel DN, Lechner A (2010) Chronic psychosocial stress promotes systemic immune activation and the development of inflammatory Th cell responses. Brain Behav Immun 24:1097–104
Shi FD, Ljunggren HG, La Cava A, Van Kaer L (2011) Organ-specific features of natural killer cells. Nat Rev Immunol 11:658–71
Sluzewska A, Sobieska M, Rybakowski JK (1997) Changes in acute-phase proteins during lithium potentiation of antidepressants in refractory depression. Neuropsychobiology 35:123–7
Szuster-Ciesielska A, Slotwinska M, Stachura A, Marmurowska-Michalowska H, Dubas-Slemp H, Bojarska-Junak A, Kandefer-Szerszen M (2008) Accelerated apoptosis of blood leukocytes and oxidative stress in blood of patients with major depression. Prog Neuro-Psychopharmacol Biol Psychiatry 32:686–94
Tansey KE, Guipponi M, Perroud N, Bondolfi G, Domenici E, Evans D, Hall SK, Hauser J, Henigsberg N, Hu X, Jerman B, Maier W, Mors O, O'Donovan M, Peters TJ, Placentino A, Rietschel M, Souery D, Aitchison KJ, Craig I, Farmer A, Wendland JR, Malafosse A, Holmans P, Lewis G, Lewis CM, Stensbol TB, Kapur S, McGuffin P, Uher R (2012) Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis. PLoS Med 9:e1001326
Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M, Team SDS (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163:28–40
Vermeiden M, Mulder PG, van den Broek WW, Bruijn JA, Birkenhager TK (2013) A double-blind randomized study comparing plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients. J Psychiatr Res 47:1337–42
Wang J, Yu L, Jiang C, Fu X, Liu X, Wang M, Ou C, Cui X, Zhou C, Wang J (2015) Cerebral ischemia increases bone marrow CD4+ CD25+ FoxP3+ regulatory T cells in mice via signals from sympathetic nervous system. Brain Behav Immun 43:172–83
Zhang Y, Zhen H, Yao W, Bian F, Mao X, Yang X, Jin S (2013) Antidepressant drug, desipramine, alleviates allergic rhinitis by regulating Treg and Th17 cells. Int J Immunopathol Pharmacol 26:107–15
Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A, McCorkle R, Seligman DA, Schmidt K (2001) The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun 15:199–226
Zunszain PA, Hepgul N, Pariante CM (2013) Inflammation and depression. Curr Top Behav Neurosci 14:135–51
We greatly appreciate Jan Bruijn for the design of the treatment trial, Annemarie Wijkhuijs, Harm de Wit, Thomas Hoogenboezem, and Angelique van Rijswijk for their technical assistance, Walter van den Broek and Esther Pluijms for their clinical care, and Siska Verploegh and Alfredo Ortigosa Aguilera for their management and database assistance.
Funding and disclosure
This study was supported by European Union EU-FP7-HEALTH-F2-2008-222963 “MOODINFLAME”. Laura Grosse was funded by EU-FP7-PEOPLE-2009-IAPP “PSYCH-AID”. Livia A. Carvalho was supported by British Council-Partek Partnership, by the British Heart Foundation, and by an ECNP Young Investigator Award. Tom K. Birkenhager receives study support and speakers' fees from Lundbeck. Hemmo A. Drexhage has received grants from the Netherlands Organisation for Health Research and Development, the European Union, the Dutch Diabetic Foundation and the JDRF; he serves/has served in advisory boards of the Netherlands Organisation for Health Research and Development and the European Union. Veerle Bergink is supported by an Erasmus University fellowship and has received funding from the Netherlands Organisation for Scientific Research (NWO, Rubicon incentive). These supporters had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.
Conflict of interest
The authors declare no conflict of interest.
Laura Grosse and Livia A. Carvalho share first authorship
Hemmo A. Drexhage and Veerle Bergink share last authorship
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Grosse, L., Carvalho, L.A., Birkenhager, T.K. et al. Circulating cytotoxic T cells and natural killer cells as potential predictors for antidepressant response in melancholic depression. Restoration of T regulatory cell populations after antidepressant therapy. Psychopharmacology 233, 1679–1688 (2016). https://doi.org/10.1007/s00213-015-3943-9
- Major depressive disorder
- Treatment reponse
- Fluorescence-activated cell sorting
- Cytotoxic T cells
- Natural killer cells
- T regulatory cells