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Exploring interleukin-6, lipopolysaccharide-binding protein and brain-derived neurotrophic factor following 12 weeks of adjunctive minocycline treatment for depression

Published online by Cambridge University Press:  23 December 2021

Kyoko Hasebe Open the ORCID record for Kyoko Hasebe [Opens in a new window] ,
Mohammadreza Mohebbi ,
Laura Gray ,
Adam J. Walker ,
Chiara C. Bortolasci ,
Alyna Turner ,
Michael Berk Open the ORCID record for Michael Berk [Opens in a new window] ,
Ken Walder ,
Michael Maes Open the ORCID record for Michael Maes [Opens in a new window]  and
Buranee Kanchanatawan
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Kyoko Hasebe
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
Mohammadreza Mohebbi
Affiliation:
Biostatistics Unit, Faculty of Health, Deakin University, Geelong, Vic, Australia
Laura Gray
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia Centre for Medical and Molecular Research, School of Medicine, Deakin University, Geelong, Vic, Australia Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Vic, Australia
Adam J. Walker
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia
Chiara C. Bortolasci
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia Centre for Medical and Molecular Research, School of Medicine, Deakin University, Geelong, Vic, Australia
Alyna Turner
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia School of Medicine and Public Health, Faculty of Health, The University of Newcastle, Callaghan, NSW, Australia
Michael Berk
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Vic, Australia Department of Psychiatry, Royal Melbourne Hospital, University of Melbourne, Parkville, Vic, Australia Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, Vic, Australia Centre of Youth Mental Health, The University of Melbourne, Parkville, Vic, Australia
Ken Walder
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia Centre for Medical and Molecular Research, School of Medicine, Deakin University, Geelong, Vic, Australia
Michael Maes
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Buranee Kanchanatawan
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Melanie M. Ashton
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia
Lesley Berk
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia Melbourne School of Population and Global Health, University of Melbourne, Carlton, Vic, Australia
Chee H. Ng
Affiliation:
Department of Psychiatry, University of Melbourne, The Melbourne Clinic, Richmond, Vic, Australia
Gin S. Malhi
Affiliation:
Faculty of Medicine and Health, Northern Clinical School, Department of Psychiatry, The University of Sydney, Sydney, NSW, Australia Academic Department of Psychiatry, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia CADE Clinic, Department of Psychiatry, Royal North Shore Hospital, St Leonards, NSW, Australia
Ajeet B. Singh
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia
Olivia M. Dean*
Affiliation:
IMPACT, the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Vic, Australia Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Vic, Australia
*
Author for correspondence: Olivia M. Dean, Email: o.dean@deakin.edu.au
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Abstract

This study aimed to explore effects of adjunctive minocycline treatment on inflammatory and neurogenesis markers in major depressive disorder (MDD). Serum samples were collected from a randomised, placebo-controlled 12-week clinical trial of minocycline (200 mg/day, added to treatment as usual) for adults (n = 71) experiencing MDD to determine changes in interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP) and brain derived neurotrophic factor (BDNF). General Estimate Equation modelling explored moderation effects of baseline markers and exploratory analyses investigated associations between markers and clinical outcomes. There was no difference between adjunctive minocycline or placebo groups at baseline or week 12 in the levels of IL-6 (week 12; placebo 2.06 ± 1.35 pg/ml; minocycline 1.77 ± 0.79 pg/ml; p = 0.317), LBP (week 12; placebo 3.74 ± 0.95 µg/ml; minocycline 3.93 ± 1.33 µg/ml; p = 0.525) or BDNF (week 12; placebo 24.28 ± 6.69 ng/ml; minocycline 26.56 ± 5.45 ng/ml; p = 0.161). Higher IL-6 levels at baseline were a predictor of greater clinical improvement. Exploratory analyses suggested that the change in IL-6 levels were significantly associated with anxiety symptoms (HAMA; p = 0.021) and quality of life (Q-LES-Q-SF; p = 0.023) scale scores. No other clinical outcomes were shown to have this mediation effect, nor did the other markers (LBP or BDNF) moderate clinical outcomes. There were no overall changes in IL-6, LBP or BDNF following adjunctive minocycline treatment. Exploratory analyses suggest a potential role of IL-6 on mediating anxiety symptoms with MDD. Future trials may consider enrichment of recruitment by identifying several markers or a panel of factors to better represent an inflammatory phenotype in MDD with larger sample size.

Keywords

brain-derived neurotrophic factorinterleukin-6lipopolysaccharide-binding proteinmajor depressive disorderminocycline
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 34 , Issue 4 , August 2022 , pp. 220 - 227
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Copyright
© The Author(s), 2021. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology

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References

Abbasi, SH, Hosseini, F, Modabbernia, A, Ashrafi, M and Akhondzadeh, S (2012) Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. Journal of Affective Disorders 141(2-3), 308–314.CrossRefGoogle ScholarPubMed
Bakunina, N, Pariante, CM and Zunszain, PA (2015) Immune mechanisms linked to depression via oxidative stress and neuroprogression. Immunology 144(3), 365–373.CrossRefGoogle ScholarPubMed
Berk, M, Walker, AJ and Nierenberg, AA (2019) Biomarker-guided anti-inflammatory therapies: from promise to reality check. JAMA Psychiatry 76(8), 779–780.CrossRefGoogle ScholarPubMed
Cai, DB, Zheng, W, Zhang, QE, Ng, CH, Ungvari, GS, Huang, X and Xiang, YT (2020) Minocycline for depressive symptoms: a meta-analysis of randomized, double-blinded, placebo-controlled trials. Psychiatric Quarterly 91(2), 451–461.CrossRefGoogle ScholarPubMed
Dean, OM, Kanchanatawan, B, Ashton, M, Mohebbi, M, Ng, CH, Maes, M, Berk, L, Sughondhabirom, A, Tangwongchai, S, Singh, AB, Mckenzie, H, Smith, DJ, Malhi, GS, Dowling, N, Berk, M (2017) Adjunctive minocycline treatment for major depressive disorder: a proof of concept trial. Australian and New Zealand Journal of Psychiatry 51(8), 829–840.CrossRefGoogle ScholarPubMed
Garrido-Mesa, N, Zarzuelo, A and Galvez, J (2013) Minocycline: far beyond an antibiotic. British Journal of Pharmacology 169(2), 337–352.CrossRefGoogle ScholarPubMed
Gonzalez-Quintela, A, Alonso, M, Campos, J, Vizcaino, L, Loidi, L and Gude, F (2013) Determinants of serum concentrations of lipopolysaccharide-binding protein (LBP) in the adult population: the role of obesity. PLOS One 8(1), e54600.CrossRefGoogle ScholarPubMed
Hasebe, K, Gray, L, Bortolasci, C, Panizzutti, B, Mohebbi, M, Kidnapillai, S, Spolding, B, Walder, K, Berk, M, Malhi, G, Dodd, S and Dean, OM (2017) Adjunctive N-acetylcysteine in depression: exploration of interleukin-6, C-reactive protein and brain-derived neurotrophic factor. Acta Neuropsychiatrica 29(6), 337–346.CrossRefGoogle ScholarPubMed
Henry, CJ, Huang, Y, Wynne, A, Hanke, M, Himler, J, Bailey, MT, Sheridan, JF and Godbout, JP (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. Journal of Neuroinflammation 5(1), 15.CrossRefGoogle ScholarPubMed
Himmerich, H, Patsalos, O, Lichtblau, N, Ibrahim, MAA and Dalton, B (2019) Cytokine research in depression: principles, challenges, and open questions. Frontiers in Psychiatry 10, 373.CrossRefGoogle ScholarPubMed
Husain, MI, Chaudhry, IB, Husain, N, Khoso, AB, Rahman, RR, Hamirani, MM, Hodsoll, J, Qurashi, I, Deakin, JF, Young, AH (2017) Minocycline as an adjunct for treatment-resistant depressive symptoms: a pilot randomised placebo-controlled trial. Journal of Psychopharmacology 31(9), 1166–1175.CrossRefGoogle ScholarPubMed
Husain, MI, Chaudhry, IB, Rahman, RR, Hamirani, MM, Qurashi, I, Khoso, AB, Deakin, JF, Husain, N and Young, AH (2015) Minocycline as an adjunct for treatment-resistant depressive symptoms: study protocol for a pilot randomised controlled trial. Trials 16(1), 410.CrossRefGoogle ScholarPubMed
Kessler, RC, Angermeyer, M, Anthony, JC, D.E.G., R, Demyttenaere, K, Gasquet, I, D.E.G., G, Gluzman, S, Gureje, O, Haro, JM, Kawakami, N, Karam, A, Levinson, D, Medina Mora, ME, Oakley Browne, MA, Posada-Villa, J, Stein, DJ, Adley Tsang, CH, Aguilar-Gaxiola, S, Alonso, J, Lee, S, Heeringa, S, Pennell, BE, Berglund, P, Gruber, MJ, Petukhova, M, Chatterji, S and Ustun, TB (2007) Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization’s World Mental Health Survey Initiative. World Psychiatry 6, 168–176.Google ScholarPubMed
Köhler, CA, Freitas, TH, Maes, M, de Andrade, NQ, Liu, CS, Fernandes, BS, Stubbs, B, Solmi, M, Veronese, N, Herrmann, N, Raison, CL, Miller, BJ, Lanctôt, KL, Carvalho, AF (2017) Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatrica Scandinavica 135(5), 373–387.CrossRefGoogle ScholarPubMed
Köhler, CA, Freitas, TH, Stubbs, B, Maes, M, Solmi, M, Veronese, N, de Andrade, NQ, Morris, G, Fernandes, BS, Brunoni, AR, Herrmann, N, Raison, CL, Miller, BJ, Lanctôt, KL, Carvalho, AF (2018) Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis. Molecular Neurobiology 55, 4195–4206.Google ScholarPubMed
Kraemer, HC, Wilson, GT, Fairburn, CG and Agras, WS (2002) Mediators and moderators of treatment effects in randomized clinical trials. Archives of General Psychiatry 59(10), 877–883.CrossRefGoogle ScholarPubMed
Lindqvist, D, Dhabhar, FS, James, SJ, Hough, CM, Jain, FA, Bersani, FS, Reus, VI, Verhoeven, JE, Epel, ES, Mahan, L, Rosser, R, Wolkowitz, OM, Mellon, SH (2017) Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology 76(Suppl. 3), 197–205.CrossRefGoogle ScholarPubMed
Liu, YN, Peng, YL, Liu, L, Wu, TY, Zhang, Y, Lian, YJ, Yang, YY, Kelley, KW, Jiang, CL, Wang, YX (2015) TNFalpha mediates stress-induced depression by upregulating indoleamine 2,3-dioxygenase in a mouse model of unpredictable chronic mild stress. European Cytokine Network 26(1), 15–25.Google Scholar
Majidi, J, Kosari-Nasab, M and Salari, AA (2016) Developmental minocycline treatment reverses the effects of neonatal immune activation on anxiety- and depression-like behaviors, hippocampal inflammation, and HPA axis activity in adult mice. Brain Research Bulletin 120(1), 1–13.CrossRefGoogle ScholarPubMed
Malhi, GS and Mann, JJ (2018) Depression. Lancet 392(10161), 2299–2312.CrossRefGoogle ScholarPubMed
Mcintyre, RS, Subramaniapillai, M, Lee, Y, Pan, Z, Carmona, NE, Shekotikhina, M, Rosenblat, JD, Brietzke, E, Soczynska, JK, Cosgrove, VE, Miller, S, Fisher, EG, Kramer, NE, Dunlap, K, Suppes, T, Mansur, RB (2019) Efficacy of adjunctive infliximab vs placebo in the treatment of adults with bipolar I/II depression: a randomized clinical trial. JAMA Psychiatry 76(8), 783–790.CrossRefGoogle ScholarPubMed
Miller, AH and Raison, CL (2015) The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature Reviews Immunology 16(1), 22–34.CrossRefGoogle Scholar
Möller, T, Bard, F, Bhattacharya, A, Biber, K, Campbell, B, Dale, E, Eder, C, Gan, L, Garden, GA, Hughes, ZA, Pearse, DD, Staal, RG, Sayed, FA, Wes, PD, Boddeke, HW (2016) Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor. Glia 64(10), 1788–1794.CrossRefGoogle ScholarPubMed
Nettis, MA, Lombardo, G, Hastings, C, Zajkowska, Z, Mariani, N, Nikkheslat, N, Wprrell, C, Enache, D, Mclaughlin, A, Kose, M, Sforzini, L, Bogdanova, A, Cleare, A, Young, AH, Pariante, CM, Mondelli, V (2021) Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial. Neuropsychopharmacol 46(5), 939–948.CrossRefGoogle ScholarPubMed
Osimo, EF, Pillinger, T, Rodriguez, IM, Khandaker, GM, Pariante, CM and Howes, OD (2020) Inflammatory markers in depression: a meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls. Brain, Behavior, and Immunity 87(1), 901–909.CrossRefGoogle ScholarPubMed
Pae, CU, Marks, DM, Han, C and Patkar, AA (2008) Does minocycline have antidepressant effect? Biomedicine & Pharmacotherapy 62(5), 308–311.CrossRefGoogle ScholarPubMed
Pape, K, Tamouza, R, Leboyer, M and Zipp, F (2019) Immunoneuropsychiatry - novel perspectives on brain disorders. Nature Reviews Neurology 15(6), 317–328.CrossRefGoogle ScholarPubMed
Rogers, GB, Keating, DJ, Young, RL, Wong, ML, Licinio, J and Wesselingh, S (2016) From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Molecular Psychiatry 21(6), 738–748.CrossRefGoogle ScholarPubMed
Rosenblat, JD and Mcintyre, RS (2018) Efficacy and tolerability of minocycline for depression: a systematic review and meta-analysis of clinical trials. Journal of Affective Disorders 227, 219–225.CrossRefGoogle ScholarPubMed
Wiedlocha, M, Marcinowicz, P, Krupa, R, Janoska-Jazdzik, M, Janus, M, Debowska, W, Mosiolek, A, Waszkiewicz, N and Szulc, A (2018) Effect of antidepressant treatment on peripheral inflammation markers - A meta-analysis. Progress in Neuro-Psychopharmacology & Biological Psychiatry 80(2–3), 217–226.CrossRefGoogle ScholarPubMed
Zazula, R, Husain, MI, Mohebbi, M, Walker, AJ, Chaudhry, IB, Khoso, AB, Ashton, MM, Agustini, B, Husain, N, Deakin, J, Young, AH Berk, M, Kanchanatawan, B, Ng, CH, Maes, M, Berk, L, Singh, AB, Malhi, GS, and Dean, OM (2020) Minocycline as adjunctive treatment for major depressive disorder: pooled data from two randomized controlled trials. Australian & New Zealand Journal of Psychiatry 55(8), 784–798.CrossRefGoogle ScholarPubMed
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