Clinical phenotypes of depressed patients with evidence of inflammation and somatic symptoms

Éimear M Foley, Joel T Parkinson, Nils Kappelmann, Golam M Khandaker, Éimear M Foley, Joel T Parkinson, Nils Kappelmann, Golam M Khandaker

Abstract

Whether depressed patients with evidence of inflammation are more appropriate candidates for immunotherapies is being tested in several clinical trials, which are selecting patients based on elevated C-reactive protein (CRP) and inflammation-related symptoms. However, studies of the clinical and phenotypic profile of depressed patients with elevated CRP are relatively scarce. We have investigated detailed clinical characteristics of 84 depressed patients, grouped as those with (CRP≥3 mg/L) and without (CRP<3 mg/L) inflammation. All patients met the International Classification of Diseases 10th Revision criteria for current depressive episode and had somatic symptoms of depression. We report that depressed patients with inflammation are more likely to be older (P=0.04), have higher body mass index (P<0.01), and be on non-selective serotonin reuptake inhibitor anti-depressants (P=0.04). After adjusting for potential confounders, the inflammation group had higher depression severity (adjusted mean difference, 8.82; 95% CI, 3.91-13.72), somatic symptoms (adjusted mean difference, 3.25; 95% CI, 1.58-4.92), state anxiety (adjusted mean difference, 9.25; 95% CI, 3.82-14.67), perceived stress (adjusted mean difference, 4.58; 95% CI, 1.98-7.18), and fatigue (adjusted mean difference, 9.71; 95% CI, 3.09-6.33), but not anhedonia. The inflamed group also had poorer quality of life (adjusted mean difference, -0.18; 95% CI, -0.32-0.05). At individual depressive symptom level, the inflammation group had increased guilty feelings (adjusted odds ratio [OR], 7.28; 95% CI, 2.09-31.17), pessimism (adjusted OR, 5.38; 95% CI, 1.53-22.73), concentration difficulties (adjusted OR, 4.56; 95% CI, 1.32-19.02), and indecisiveness (adjusted OR, 4.21; 95% CI, 1.15-18.54). Our findings highlight the clinical features associated with inflammation in depressed patients with somatic symptoms, including poor quality of life, supporting the need for intervention targeting this group. These results could also aid patient and outcome selection in future clinical trials testing immunotherapies in depression. Replication of these findings in larger samples is required.

Keywords: Anxiety; C-Reactive protein; Depression; Fatigue; Inflammation; Quality of life.

Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Cases of ICD-10 current mild, moderate, and severe depressive episode grouped by serum hs-CRP level. ICD-10, International Classification of Diseases 10th Revision; hs-CRP, high-sensitivity C-reactive protein.
Fig. 2
Fig. 2
Adjusted (i.e., age, sex, BMI, and current antidepressant medication type) Odds Ratios (95% CI) for individual depressive symptoms in depressed patients with somatic symptoms and evidence of inflammation. OR, Odds ratio.

References

    1. Beck A.T., Steer R.A., Brown G.K. 1996. Manual for the BDI-II. San Antonio, TX.
    1. Bekhbat M., Chu K., Le N.-A., Woolwine B.J., Haroon E., Miller A.H., Felger J.C. Glucose and lipid-related biomarkers and the antidepressant response to infliximab in patients with treatment-resistant depression. Psychoneuroendocrinology. 2018;98:222–229. doi: 10.1016/j.psyneuen.2018.09.004.
    1. Benjamini Y., Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing yoav Benjamini. Yosef Hochberg Journal of the Royal Statistical Society . Series B ( Methodological ) 1995;57(No . 1):289–300. ( 1995), pp . 57.
    1. Bond A., Lader M. The use of analogue scales in rating subjective feelings. Br. J. Med. Psychol. 1974;47:211–218. doi: 10.1111/j.2044-8341.1974.tb02285.x.
    1. Brydon L., Harrison N.A., Walker C., Steptoe A., Critchley H.D. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol. Psychiatr. 2008;63:1022–1029. doi: 10.1016/j.biopsych.2007.12.007.
    1. Capuron L., Gumnick J.F., Musselman D.L., Lawson D.H., Reemsnyder A., Nemeroff C.B., Miller A.H. Neurobehavioral effects of interferon-α in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26:643–652. doi: 10.1016/S0893-133X(01)00407-9.
    1. Capuron L., Pagnoni G., Drake D.F., Woolwine B.J., Spivey J.R., Crowe R.J., Votaw J.R., Goodman M.M., Miller A.H. Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch. Gen. Psychiatr. 2012;69:1044–1053. doi: 10.1001/archgenpsychiatry.2011.2094.
    1. Carvalho L.A., Torre J.P., Papadopoulos A.S., Poon L., Juruena M.F., Markopoulou K., Cleare A.J., Pariante C.M. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J. Affect. Disord. 2013;148:136–140.
    1. Chu A.L., Stochl J., Lewis G., Zammit S., Jones P.B., Khandaker G.M. Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort. Brain Behav. Immun. 2019;76:74–81.
    1. Cohen S., Kamarck T., Mermelstein R. A global measure of perceived stress. J. Health Soc. Behav. 1983;24:385–396.
    1. Cronbach L.J. Coefficient alpha and the internal structure of tests. Psychometrika. 1951;16:297–334. doi: 10.1007/BF02310555.
    1. Dantzer R., Heijnen C.J., Kavelaars A., Laye S., Capuron L. The neuroimmune basis of fatigue. Trends Neurosci. 2014;37:39–46. doi: 10.1016/j.tins.2013.10.003.
    1. Duivis H.E., Vogelzangs N., Kupper N., de Jonge P., Penninx B.W.J.H., Jonge P. De, Penninx B.W.J.H. Differential association of somatic and cognitive symptoms of depression and anxiety with inflammation : findings from The Netherlands Study of Depression and Anxiety ( NESDA ) Psychoneuroendocrinology. 2013;38:1573–1585. doi: 10.1016/j.psyneuen.2013.01.002.
    1. Eisenberger N.I., Berkman E.T., Inagaki T.K., Rameson L.T., Mashal N.M., Irwin M.R. Inflammation-Induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol. Psychiatr. 2010;68:748–754. doi: 10.1016/j.biopsych.2010.06.010.
    1. EuroQol Research Foundation . 2018. EQ-5D-3L User Guide.
    1. Faugere M., Micoulaud-Franchi J., Faget-Agius C., Lançon C., Cermolacce M., Richieri R. Quality of life is associated with chronic inflammation in depression. A cross-sectional study. 2018;227:494–497. doi: 10.1016/j.jad.2017.11.061.
    1. Felger J.C., Li Z., Haroon E., Woolwine B.J., Jung M.Y., Hu X., Miller A.H. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol. Psychiatr. 2016;21:1358–1365. doi: 10.1038/mp.2015.168.
    1. Felger J.C., Mun J., Kimmel H.L., Nye J.A., Drake D.F., Hernandez C.R., Freeman A.A., Rye D.B., Goodman M.M., Howell L.L., Miller A.H. Chronic interferon-a decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology. 2013;38:2179–2187. doi: 10.1038/npp.2013.115.
    1. Haapakoski R., Mathieu J., Ebmeier K.P., Alenius H., Kivimäki M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav. Immun. 2015;49:206–215. doi: 10.1016/j.bbi.2015.06.001.
    1. Häfner S., Baghai T.C., Eser D., Schüle C., Rupprecht R., Bondy B., Bedarida G., Schacky C. von. C-reactive protein is associated with polymorphisms of the angiotensin-converting enzyme gene in major depressed patients. J. Psychiatr. Res. 2008;42:163–165. doi: 10.1016/j.jpsychires.2007.02.002.
    1. Haroon E., Fleischer C.C., Felger J.C., Chen X., Woolwine B.J., Patel T., Hu X.P., Miller A.H. Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Mol. Psychiatr. 2016;21:1351–1357. doi: 10.1038/mp.2015.206.
    1. Harrison N.A., Cercignani M., Voon V., Critchley H.D. Effects of inflammation on Hippocampus and substantia nigra responses to novelty in healthy human participants. Neuropsychopharmacology. 2015:831–838. doi: 10.1038/npp.2014.222.
    1. Hirschfeld R.M.A. The comorbidity of major depression and anxiety disorders: recognition and management in primary care. Prim. Care Companion J. Clin. Psychiatry. 2001;3:244–254.
    1. Jokela M., Virtanen M., Batty G.D., Kivimäki M. Inflammation and specific symptoms of depression. JAMA Psychiatry. 2016;73:87. doi: 10.1001/jamapsychiatry.2015.1977.
    1. Kanter J.W., Busch A.M., Weeks C.E., Landes S.J. The nature of clinical depression: symptoms, syndromes, and behavior analysis. Behav. Anal. 2008;31:1–21. doi: 10.1007/BF03392158.
    1. Kappelmann N., Lewis G., Dantzer R., Jones P.B., Khandaker G.M. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol. Psychiatr. 2018;23:335–343. doi: 10.1038/mp.2016.167.
    1. Kennedy S.H. Core symptoms of major depressive disorder: relevance to diagnosis and treatment. Dialogues Clin. Neurosci. 2008;10:271–277. doi: 10.31887/dcns.2008.10.3/shkennedy.
    1. Khandaker G.M., Oltean B.P., Kaser M., Dibben C.R.M., Ramana R., Jadon D.R., Dantzer R., Coles A.J., Lewis G., Jones P.B. Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation. BMJ Open. 2018;8 doi: 10.1136/bmjopen-2018-025333.
    1. Khandaker G.M., Pearson R.M., Zammit S., Lewis G., Jones P.B. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life a population-based longitudinal study. JAMA Psychiatry. 2014;71:1121–1128. doi: 10.1001/jamapsychiatry.2014.1332.
    1. Khandaker G.M., Zammit S., Burgess S., Lewis G., Jones P.B. Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort. Brain Behav. Immun. 2018;69:264–272. doi: 10.1016/j.bbi.2017.11.020.
    1. Köhler-Forsberg O., Buttenschøn H.N., Tansey K.E., Maier W., Hauser J., Dernovsek M.Z., Henigsberg N., Souery D., Farmer A., Rietschel M., McGuffin P., Aitchison K.J., Uher R., Mors O. Association between C-reactive protein (CRP) with depression symptom severity and specific depressive symptoms in major depression. Brain Behav. Immun. 2017;62:344–350. doi: 10.1016/j.bbi.2017.02.020.
    1. Köhler-Forsberg O., Lydholm C.N., Hjorthøj C., Nordentoft M., Mors O., Benros M.E. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr. Scand. 2019;139:404–419. doi: 10.1111/acps.13016.
    1. Lee C.H., Giuliani F. The role of inflammation in depression and fatigue. Front. Immunol. 2019;10:1696. doi: 10.3389/fimmu.2019.01696.
    1. Lenox-Smith A., Macdonald M.T.B., Reed C., Tylee A., Peveler R., Quail D., Wildgust H.J. Quality of life in depressed patients in UK primary care: the FINDER study. Neurol. Ther. 2013;2:25–42. doi: 10.1007/s40120-013-0006-1.
    1. Lewis G. Assessing psychiatric disorder with a human interviewer or a computer. J. Epidemiol. Community Health. 1994;48:207–210. doi: 10.1136/jech.48.2.207.
    1. Liu Y., Blackwood D.H., Caesar S., de Geus E.J.C., Farmer A., Ferreira M.A.R., Ferrier I.N., Fraser C., Gordon-Smith K., Green E.K., Grozeva D., Gurling H.M., Hamshere M.L., Heutink P., Holmans P.A., Hoogendijk W.J., Hottenga J.J., Jones L., Jones I.R., Kirov G., Lin D., McGuffin P., Moskvina V., Nolen W.A., Perlis R.H., Posthuma D., Scolnick E.M., Smit A.B., Smit J.H., Smoller J.W., St Clair D., van Dyck R., Verhage M., Willemsen G., Young A.H., Zandbelt T., Boomsma D.I., Craddock N., O’Donovan M.C., Owen M.J., Penninx B.W.J.H., Purcell S., Sklar P., Sullivan P.F., Wellcome Trust Case-Control Consortium Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder. Mol. Psychiatr. 2011 doi: 10.1038/mp.2009.107.
    1. Meyers C.A., Albitar M., Estey E. Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer. 2005;104:788–793. doi: 10.1002/cncr.21234.
    1. Milaneschi Y., Kappelmann N., Ye Z., Lamers F., Moser S., Jones P.B., Burgess S., Penninx B.W.J.H., Khandaker G.M. Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK biobank and NESDA cohorts. medRxiv. 2021 doi: 10.1101/2021.01.08.20248710.
    1. Milaneschi Y., Lamers F., Berk M., Penninx B.W.J.H. Depression heterogeneity and its biological underpinnings: toward immunometabolic depression. Biol. Psychiatr. 2020;88:369–380. doi: 10.1016/j.biopsych.2020.01.014.
    1. Osimo E.F., Baxter L.J., Lewis G., Jones P.B., Khandaker G.M. Prevalence of low-grade inflammation in depression: a systematic review and meta-Analysis of CRP levels. Psychol. Med. 2019;49:1958–1970.
    1. Pearson T.A., Mensah G.A., Alexander R.W., Anderson J.L., Cannon R.O., Criqui M., Fadl Y.Y., Fortmann S.P., Hong Y., Myers G.L., Rifai N., Smith S.C., Taubert K., Tracy R.P., Vinicor F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511. doi: 10.1161/01.CIR.0000052939.59093.45.
    1. Pedraz-Petrozzi B., Neumann E., Sammer G. Pro-inflammatory markers and fatigue in patients with depression: a case-control study. Sci. Rep. 2020;10:1–12. doi: 10.1038/s41598-020-66532-6.
    1. R Core Team . 2020. R: A Language Environment for Statistical Computing.
    1. Raison C.L., Rutherford R.E., Woolwine B.J., Shuo C., Schettler P., Drake D.F., Haroon E., Miller A.H. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31–41. doi: 10.1001/2013.jamapsychiatry.4.
    1. Smets E.M., Garssen B., Bonke B., De Haes J.C. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J. Psychosom. Res. 1995;39:315–325. doi: 10.1016/0022-3999(94)00125-o.
    1. Snaith R.P., Hamilton M., Morley S., Humayan A., Hargreaves D., Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br. J. Psychiatry. 1995;167:99–103. doi: 10.1192/bjp.167.1.99.
    1. Speilberger C.D., Gorsuch R.L., Lushene R., Vagg P.R., Jacobs G.A. Consulting Psychologists Press; Palo Alto, CA: 1983. Manual for State-Trait Anxiety Inventory.
    1. Stewart J.C., Rand K.L., Muldoon M.F., Kamarck T.W., Karmack T.W. A prospective evaluation OF the directionality OF the depression-inflammation relationship. Brain Behav. Immun. 2009;23:936–944. doi: 10.1016/j.bbi.2009.04.011.A.
    1. Wang A.K., Miller B.J. Meta-analysis of cerebrospinal fluid cytokine and tryptophan catabolite alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder, and depression. Schizophr. Bull. 2018;44:75–83. doi: 10.1093/schbul/sbx035.
    1. Wang Y.P., Gorenstein C. Assessment of depression in medical patients: a systematic review of the utility of the Beck Depression Inventory-II. Clinics. 2013;68:1274–1287. doi: 10.6061/clinics/2013(09)15.
    1. Weinberger J.F., Raison C.L., Rye D.B., Montague A.R., Woolwine B.J., Felger J.C., Haroon E., Miller A.H. Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation. Brain Behav. Immun. 2015;47:193–200. doi: 10.1016/j.bbi.2014.12.016.
    1. Whale R., Fialho R., Field A.P., Campbell G., Tibble J., Harrison N.A., Rolt M. Factor analyses differentiate clinical phenotypes of idiopathic and interferon-alpha-induced depression. Brain Behav. Immun. 2019;80:519–524. doi: 10.1016/j.bbi.2019.04.035.
    1. Winer E.S., Jordan D.G., Collins A.C. Conceptualizing anhedonias and implications for depression treatments. Psychol. Res. Behav. Manag. 2019;12:325–335. doi: 10.2147/PRBM.S159260.
    1. Wittenberg G.M., Stylianou A., Zhang Y., Sun Y., Gupta A., Jagannatha P.S., Wang D., Hsu B., Curran M.E., Khan S., Chen G., Bullmore E.T., Drevets W.C., Vértes P.E., Cardinal R., Richardson S., Leday G., Freeman T., Hume D., Regan T., Wu Z., Pariante C., Cattaneo A., Zunszain P., Borsini A., Stewart R., Chandran D., Carvalho L., Bell J., Souza-Teodoro L.H., Perry H., Harrison N., Jones D., Henderson R.B., Chen G., Bullmore E.T., Drevets W.C. Effects of immunomodulatory drugs on depressive symptoms: a mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders. Mol. Psychiatr. 2020;25:1275–1285. doi: 10.1038/s41380-019-0471-8.
    1. Ye Z., Kappelmann N., Moser S., Smith G.D., Jones P.B., Khandaker G.M. Role of inflammation in depression and Anxiety : tests for disorder specificity , linearity and potential causality of association in the UK biobank. medRxiv. 2021:1–25. doi: 10.1101/2021.02.02.21250987.

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