The hypothalamic–pituitary–adrenal (HPA) axis and the inflammatory response system have been suggested as pathophysiological mechanisms implicated in the etiology of major depressive disorder (MDD). Although meta-analyses do confirm associations between depression and these biological systems, effect sizes vary greatly among individual studies. A potentially important factor explaining variability is heterogeneity of MDD. Aim of this study was to evaluate the association between depressive subtypes (based on latent class analysis) and biological measures. Data from 776 persons from the Netherlands Study of Depression and Anxiety, including 111 chronic depressed persons with melancholic depression, 122 with atypical depression and 543 controls were analyzed. Inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor-α), metabolic syndrome components, body mass index (BMI), saliva cortisol awakening curves (area under the curve with respect to the ground (AUCg) and with respect to the increase (AUCi)), and diurnal cortisol slope were compared among groups. Persons with melancholic depression had a higher AUCg and higher diurnal slope compared with persons with atypical depression and with controls. Persons with atypical depression had significantly higher levels of inflammatory markers, BMI, waist circumference and triglycerides, and lower high-density lipid cholesterol than persons with melancholic depression and controls. This study confirms that chronic forms of the two major subtypes of depression are associated with different biological correlates with inflammatory and metabolic dysregulation in atypical depression and HPA-axis hyperactivity in melancholic depression. The data provide further evidence that chronic forms of depressive subtypes differ not only in their symptom presentation, but also in their biological correlates. These findings have important implications for future research on pathophysiological pathways of depression and treatment.
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Stetler C, Miller GE . Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med 2011; 73: 114–126.
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67: 446–457.
Howren MB, Lamkin DM, Suls J . Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71: 171–186.
Alesci S, Martinez PE, Kelkar S, Ilias I, Ronsaville DS, Listwak SJ et al. Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. J Clin Endocrinol Metab 2005; 90: 2522–2530.
Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BW et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry 2010; 67: 220–229.
Papakostas GI, Ongur D, Iosifescu DV, Mischoulon D, Fava M . Cholesterol in mood and anxiety disorders: review of the literature and new hypotheses. Eur Neuropsychopharmacol 2004; 14: 135–142.
van Reedt Dortland AK, Giltay EJ, van Veen T, van Pelt J, Zitman FG, Penninx BW . Associations between serum lipids and major depressive disorder: results from the Netherlands Study of Depression and Anxiety (NESDA). J Clin Psychiatry 2010; 71: 729–736.
Kahl KG, Greggersen W, Schweiger U, Cordes J, Balijepalli C, Losch C et al. Prevalence of the metabolic syndrome in unipolar major depression. Eur Arch Psychiatry Clin Neurosci 2012; 262: 313–320.
Skilton MR, Moulin P, Terra JL, Bonnet F . Associations between anxiety, depression, and the metabolic syndrome. Biol Psychiatry 2007; 62: 1251–1257.
Knorr U, Vinberg M, Kessing LV, Wetterslev J . Salivary cortisol in depressed patients versus control persons: a systematic review and meta-analysis. Psychoneuroendocrinology 2010; 35: 1275–1286.
Anisman H, Ravindran AV, Griffiths J, Merali Z . Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features. Mol Psychiatry 1999; 4: 182–188.
Gold PW, Chrousos GP . Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 2002; 7: 254–275.
Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci USA 2000; 97: 325–330.
Yoon HK, Kim YK, Lee HJ, Kwon DY, Kim L . Role of cytokines in atypical depression. Nord J Psychiatry 2012; 66: 183–188.
Karlovic D, Serretti A, Vrkic N, Martinac M, Marcinko D . Serum concentrations of CRP, IL-6, TNF-alpha and cortisol in major depressive disorder with melancholic or atypical features. Psychiatry Res 2012; 198: 74–80.
Huang TL, Lee CT . T-helper 1/T-helper 2 cytokine imbalance and clinical phenotypes of acute-phase major depression. Psychiatry Clin Neurosci 2007; 61: 415–420.
Kaestner F, Hettich M, Peters M, Sibrowski W, Hetzel G, Ponath G et al. Different activation patterns of proinflammatory cytokines in melancholic and non-melancholic major depression are associated with HPA axis activity. J Affect Disord 2005; 87: 305–311.
Lamers F, de Jonge P, Nolen WA, Smit JH, Zitman FG, Beekman AT et al. Identifying depressive subtypes in a large cohort study: results from the Netherlands Study of Depression and Anxiety (NESDA). J Clin Psychiatry 2010; 71: 1582–1589.
Sullivan PF, Prescott CA, Kendler KS . The subtypes of major depression in a twin registry. J Affect Disord 2002; 68: 273–284.
Harald B, Gordon P . Meta-review of depressive subtyping models. J Affect Disord 2011; 139: 126–140.
Lamers F, Rhebergen D, Merikangas KR, de Jonge P, Beekman ATF, Penninx B . Stability and transitions of depressive subtypes over 2-year follow-up. Psychol Med 2012; 17: 1–11.
Capuron L, Su S, Miller AH, Bremner JD, Goldberg J, Vogt GJ et al. Depressive symptoms and metabolic syndrome: is inflammation the underlying link? Biol Psychiatry 2008; 64: 896–900.
Penninx BWJH, Beekman ATF, Smit JH, Zitman FG, Nolen WA, Spinhoven P et al. The Netherlands Study of Depression and Anxiety (NESDA): rationale, objectives and methods. Int J Methods Psychiatr Res 2008; 17: 121–140.
World Health Organization. Composite International Diagnostic Interview, Core version 2.1: Interviewer′s Manual. World Health Organization: Sydney, Australia, 1997.
Thase ME . Atypical depression: useful concept, but it’s time to revise the DSM-IV criteria. Neuropsychopharmacology 2009; 34: 2633–2641.
Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D . Atypical depression: a reappraisal. Am J Psychiatry 2002; 159: 1470–1479.
Posternak MA, Zimmerman M . Partial validation of the atypical features subtype of major depressive disorder. Arch Gen Psychiatry 2002; 59: 70–76.
Angst J, Gamma A, Sellaro R, Zhang H, Merikangas K . Toward validation of atypical depression in the community: results of the Zurich cohort study. J Affect Disord 2002; 72: 125–138.
Sullivan PF, Kessler RC, Kendler KS . Latent class analysis of lifetime depressive symptoms in the national comorbidity survey. Am J Psychiatry 1998; 155: 1398–1406.
Monroe SM, Harkness KL . Recurrence in major depression: a conceptual analysis. Psychol Rev 2011; 118: 655–674.
Monroe SM, Harkness KL . Is depression a chronic mental illness? Psychol Med 2012; 42: 899–902.
Levinson DF, Zubenko GS, Crowe RR, DePaulo RJ, Scheftner WS, Weissman MM et al. Genetics of recurrent early-onset depression (GenRED): design and preliminary clinical characteristics of a repository sample for genetic linkage studies. Am J Med Genet B Neuropsychiatr Genet 2003; 119B: 118–130.
National Cholesterol Education P. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497.
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112: 2735–2752.
Kirschbaum C, Hellhammer DH . Salivary cortisol in psychoneuroendocrine research: recent developments and applications. Psychoneuroendocrinology 1994; 19: 313–333.
van Aken MO, Romijn JA, Miltenburg JA, Lentjes EG . Automated measurement of salivary cortisol. Clin Chem 2003; 49: 1408–1409.
Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH . Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology 2003; 28: 916–931.
Vreeburg SA, Kruijtzer BP, van Pelt J, van Dyck R, DeRijk RH, Hoogendijk WJ et al. Associations between sociodemographic, sampling and health factors and various salivary cortisol indicators in a large sample without psychopathology. Psychoneuroendocrinology 2009; 34: 1109–1120.
Jabben N, Nolen WA, Smit JH, Vreeburg SA, Beekman AT, Penninx BW . Co-occurring manic symptomatology influences HPA axis alterations in depression. J Psychiatr Res 2011; 45: 1208–1213.
Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH . The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 1996; 26: 477–486.
Lyketsos CG, Nestadt G, Cwi J, Heithoff K, Eaton WW . The life chart interview: a standardized method to describe the course of psychopathology. Int J Methods Psychiatr Res 1994; 4: 143–155.
Fyer AJ, Weissman MM . Genetic linkage study of panic: clinical methodology and description of pedigrees. Am J Med Genet 1999; 88: 173–181.
Manthey L, Leeds C, Giltay EJ, van Veen T, Vreeburg SA, Penninx BW et al. Antidepressant use and salivary cortisol in depressive and anxiety disorders. Eur Neuropsychopharmacol 2011; 21: 691–699.
Vogelzangs N, Duivis HE, Beekman ATF, Kluft C, Neuteboom J, Hoogendijk WJ et al. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Translational Psychiatry 2012; 2: e79.
van Reedt Dortland AK, Giltay EJ, van Veen T, Zitman FG, Penninx BW . Metabolic syndrome abnormalities are associated with severity of anxiety and depression and with tricyclic antidepressant use. Acta Psychiatr Scand 2010; 122: 30–39.
Licht CM, de Geus EJ, Seldenrijk A, van Hout HP, Zitman FG, van Dyck R et al. Depression is associated with decreased blood pressure, but antidepressant use increases the risk for hypertension. Hypertension 2009; 53: 631–638.
Jo YH, Talmage DA, Role LW . Nicotinic receptor-mediated effects on appetite and food intake. J Neurobiol 2002; 53: 618–632.
Hasler G, Pine DS, Gamma A, Milos G, Ajdacic V, Eich D et al. The associations between psychopathology and being overweight: a 20-year prospective study. Psychol Med 2004; 34: 1047–1057.
Vazquez-Vela ME, Torres N, Tovar AR . White adipose tissue as endocrine organ and its role in obesity. Arch Med Res 2008; 39: 715–728.
Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001; 58: 445–452.
Wright CE, Strike PC, Brydon L, Steptoe A . Acute inflammation and negative mood: mediation by cytokine activation. Brain Behav Immun 2005; 19: 345–350.
Shelton RC, Miller AH . Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. Prog Neurobiol 2010; 91: 275–299.
Miller AH, Maletic V, Raison CL . Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741.
Raedler TJ . Inflammatory mechanisms in major depressive disorder. Curr Opin Psychiatry 2011; 24: 519–525.
Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA . Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol 2002; 90: 1279–1283.
Gimeno D, Kivimaki M, Brunner EJ, Elovainio M, De Vogli R, Steptoe A et al. Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med 2009; 39: 413–423.
Raison CL, Capuron L, Miller AH . Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24–31.
Maes M . Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 664–675.
Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 2006; 11: 680–684.
Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N . Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol 2006; 21: 227–231.
McKay MS, Zakzanis KK . The impact of treatment on HPA axis activity in unipolar major depression. J Psychiatr Res 2010; 44: 183–192.
Giles DE, Roffwarg HP, Schlesser MA, Rush AJ . Which endogenous depressive symptoms relate to REM latency reduction? Biol Psychiatry 1986; 21: 473–482.
Antonijevic I . HPA axis and sleep: identifying subtypes of major depression. Stress 2008; 11: 15–27.
Armitage R . Sleep and circadian rhythms in mood disorders. Acta Psychiatr Scand Suppl 2007; 104–115.
Angst J, Gamma A, Benazzi F, Silverstein B, Ajdacic-Gross V, Eich D et al. Atypical depressive syndromes in varying definitions. Eur Arch Psychiatry Clin Neurosci 2006; 256: 44–54.
The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Scientific Institute for Quality of Healthcare (IQ healthcare), Netherlands Institute for Health Services Research (NIVEL) and Netherlands Institute of Mental Health and Addiction (Trimbos). Biomarker funding was provided by the Neuroscience Campus Amsterdam and the Netherlands Organisation for Scientific research (VIDI project). BWJHP is supported by a VICI grant from the Netherlands Organisation for Scientific research. FL is supported by a Rubicon fellowship from the Netherlands Organisation for Scientific research and by a Supplemental Intramural Research Training Award from the National Institute of Mental Health, Genetic Epidemiology Research Branch. The views and opinions expressed in this article are ours and should not be construed to represent the views of any of the sponsoring organizations, agencies or US Government.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Lamers, F., Vogelzangs, N., Merikangas, K. et al. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry 18, 692–699 (2013). https://doi.org/10.1038/mp.2012.144
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