Effects of immunomodulatory drugs on depressive symptoms: A mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
29
12
2017
accepted:
24
06
2019
revised:
14
06
2019
pubmed:
21
8
2019
medline:
10
3
2021
entrez:
21
8
2019
Statut:
ppublish
Résumé
Activation of the innate immune system is commonly associated with depression. Immunomodulatory drugs may have efficacy for depressive symptoms that are co-morbidly associated with inflammatory disorders. We report a large-scale re-analysis by standardized procedures (mega-analysis) of patient-level data combined from 18 randomized clinical trials conducted by Janssen or GlaxoSmithKline for one of nine disorders (N = 10,743 participants). Core depressive symptoms (low mood, anhedonia) were measured by the Short Form Survey (SF-36) or the Hospital Anxiety and Depression Scale (HADS), and participants were stratified into high (N = 1921) versus low-depressive strata based on baseline ratings. Placebo-controlled change from baseline after 4-16 weeks of treatment was estimated by the standardized mean difference (SMD) over all trials and for each subgroup of trials targeting one of 7 mechanisms (IL-6, TNF-α, IL-12/23, CD20, COX2, BLγS, p38/MAPK14). Patients in the high depressive stratum showed modest but significant effects on core depressive symptoms (SMD = 0.29, 95% CI [0.12-0.45]) and related SF-36 measures of mental health and vitality. Anti-IL-6 antibodies (SMD = 0.8, 95% CI [0.20-1.41]) and an anti-IL-12/23 antibody (SMD = 0.48, 95% CI [0.26-0.70]) had larger effects on depressive symptoms than other drug classes. Adjustments for physical health outcome marginally attenuated the average treatment effect on depressive symptoms (SMD = 0.20, 95% CI: 0.06-0.35), but more strongly attenuated effects on mental health and vitality. Effects of anti-IL-12/23 remained significant and anti-IL-6 antibodies became a trend after controlling for physical response to treatment. Novel immune-therapeutics can produce antidepressant effects in depressed patients with primary inflammatory disorders that are not entirely explained by treatment-related changes in physical health.
Identifiants
pubmed: 31427751
doi: 10.1038/s41380-019-0471-8
pii: 10.1038/s41380-019-0471-8
pmc: PMC7244402
doi:
Substances chimiques
Antidepressive Agents
0
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1275-1285Subventions
Organisme : Medical Research Council
ID : G108/603
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/J002739/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L014815/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N029488/1
Pays : United Kingdom
Investigateurs
Petra E Vértes
(PE)
Rudolf Cardinal
(R)
Sylvia Richardson
(S)
Gwenael Leday
(G)
Tom Freeman
(T)
David Hume
(D)
Tim Regan
(T)
Zhaozong Wu
(Z)
Carmine Pariante
(C)
Annamaria Cattaneo
(A)
Patricia Zunszain
(P)
Alessandra Borsini
(A)
Robert Stewart
(R)
David Chandran
(D)
Livia Carvalho
(L)
Joshua Bell
(J)
Luis Henrique Souza-Teodoro
(LH)
Hugh Perry
(H)
Neil Harrison
(N)
Declan Jones
(D)
Robert B Henderson
(RB)
Références
Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71:171–86.
pubmed: 19188531
Vogelzangs N, Duivis HE, Beekman AT, Kluft C, Neuteboom J, Hoogendijk W, et al. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry. 2012;2:e79.
doi: 10.1038/tp.2012.8
Liu Y, Ho RC-M, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression. J Affect Disord. 2012;139:230–9.
doi: 10.1016/j.jad.2011.08.003
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;67:446–57.
doi: 10.1016/j.biopsych.2009.09.033
Mikova O, Yakimova R, Bosmans E, Kenis G, Maes M. Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Eur Neuropsychopharmacol. 2001;11:203–8.
doi: 10.1016/S0924-977X(01)00081-5
Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord. 2013;150:736–44.
doi: 10.1016/j.jad.2013.06.004
Lindqvist D, Janelidze S, Erhardt S, Träskman‐Bendz L, Engström G, Brundin L. CSF biomarkers in suicide attempters–a principal component analysis. Acta Psychiatr Scand. 2011;124:52–61.
doi: 10.1111/j.1600-0447.2010.01655.x
Lindqvist D, Janelidze S, Hagell P, Erhardt S, Samuelsson M, Minthon L, et al. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry. 2009;66:287–92.
doi: 10.1016/j.biopsych.2009.01.030
Frodl T, Carballedo A, Hughes M, Saleh K, Fagan A, Skokauskas N, et al. Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder. Transl Psychiatry. 2012;2:e88.
doi: 10.1038/tp.2012.14
Yirmiya R, Rimmerman N, Reshef R. Depression as a microglial disease. Trends Neurosci. 2015;38:637–58.
doi: 10.1016/j.tins.2015.08.001
Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268–75.
doi: 10.1001/jamapsychiatry.2014.2427
Bonaccorso S, Puzella A, Marino V, Pasquini M, Biondi M, Artini M, et al. Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms. Psychiatry Res. 2001;105:45–55.
doi: 10.1016/S0165-1781(01)00315-8
Raison CL, Borisov AS, Majer M, Drake DF, Pagnoni G, Woolwine BJ, et al. Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biol Psychiatry. 2009;65:296–303.
doi: 10.1016/j.biopsych.2008.08.010
Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA. 2014;111:16136–41.
doi: 10.1073/pnas.1415191111
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. 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
Inamdar A, Merlo-Pich E, Gee M, Makumi C, Mistry P, Robertson J, et al. Evaluation of antidepressant properties of the p38 MAP kinase inhibitor losmapimod (GW856553) in Major Depressive Disorder: Results from two randomised, placebo-controlled, double-blind, multicentre studies using a Bayesian approach. J Psychopharmacol. 2014;28:570–81.
doi: 10.1177/0269881114529377
Köhler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71:1381–91.
doi: 10.1001/jamapsychiatry.2014.1611
Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2018;23:335–43.
doi: 10.1038/mp.2016.167
Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367:29–35.
doi: 10.1016/S0140-6736(05)67763-X
Menter A, Augustin M, Signorovitch J, Andrew PY, Wu EQ, Gupta SR, et al. The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: a randomized clinical trial. J Am Acad Dermatol. 2010;62:812–8.
doi: 10.1016/j.jaad.2009.07.022
Langley RG, Feldman SR, Han C, Schenkel B, Szapary P, Hsu M-C, et al. Ustekinumab significantly improves symptoms of anxiety, depression, and skin-related quality of life in patients with moderate-to-severe psoriasis: results from a randomized, double-blind, placebo-controlled phase III trial. J Am Acad Dermatol. 2010;63:457–65.
doi: 10.1016/j.jaad.2009.09.014
Ware Jr JE. SF-36 health survey update. Spine. 2000;25:3130–9.
doi: 10.1097/00007632-200012150-00008
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67:361–70.
doi: 10.1111/j.1600-0447.1983.tb09716.x
Gueorguieva R, Krystal JH. Move over ANOVA: Progress in analyzing repeated measures data and its reflection in papers published in the Archives of General Psychiatry. Arch Gen Psychiatry. 2004;61:310–7.
doi: 10.1001/archpsyc.61.3.310
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol psychiatry. 2009;65:732–41.
doi: 10.1016/j.biopsych.2008.11.029
Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.
doi: 10.1016/j.it.2005.11.006
Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. Jama. 2010;303:47–53.
doi: 10.1001/jama.2009.1943
Köhler CA, Freitas TH, Maes MD, De Andrade NQ, Liu CS, Fernandes BS, et al. Peripheral cytokine and chemokine alterations in depression: a meta‐analysis of 82 studies. Acta Psychiatr Scand. 2017;135:373–87.
doi: 10.1111/acps.12698
Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine. 1997;9:853–8.
doi: 10.1006/cyto.1997.0238
O’Brien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res. 2007;41:326–31.
doi: 10.1016/j.jpsychires.2006.05.013
Lee K-M, Kim Y-K. The role of IL-12 and TGF-β1 in the pathophysiology of major depressive disorder. Int Immunopharmacol. 2006;6:1298–304.
doi: 10.1016/j.intimp.2006.03.015
Kim Y, Suh I, Kim H, Han C, Lim C, Choi S, et al. The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Mol Psychiatry. 2002;7:1107–14.
doi: 10.1038/sj.mp.4001084