PAID study design on the role of PKC activation in immune/inflammation-related depression: a randomised placebo-controlled trial protocol

Xiaoyun Guo, Ruizhi Mao, Lvchun Cui, Fan Wang, Rubai Zhou, Yun Wang, Jia Huang, Yuncheng Zhu, Yamin Yao, Guoqing Zhao, Zezhi Li, Jun Chen, Jinhui Wang, Yiru Fang, Xiaoyun Guo, Ruizhi Mao, Lvchun Cui, Fan Wang, Rubai Zhou, Yun Wang, Jia Huang, Yuncheng Zhu, Yamin Yao, Guoqing Zhao, Zezhi Li, Jun Chen, Jinhui Wang, Yiru Fang

Abstract

Background: Inflammation that is mediated by microglia activation plays an important role in the pathogenesis of depression. Microglia activation can lead to an increase in the levels of proinflammatory cytokines, including TNF-α, which leads to neuronal apoptosis in the specific neural circuits of some brain regions, abnormal cognition and treatment-resistant depression (TRD). Protein kinase C (PKC) is a key regulator of the microglia activation process. We assume that the abnormality in PKC might result in abnormal microglia activation, neuronal apoptosis, significant changes in emotional and cognitive neural circuits, and TRD. In the current study, we plan to target at the PKC signal pathway to improve the TRD treatment outcome.

Methods and analysis: This is a 12-week, ongoing, randomised, placebo-controlled trial. Patients with TRD (N=180) were recruited from Shanghai Mental Health Center, Shanghai Jiao Tong University. Healthy control volunteers (N=60) were recruited by advertisement. Patients with TRD were randomly assigned to 'escitalopram+golimumab (TNF-α inhibitor)', 'escitalopram+calcium tablet+vitamin D (PKC activator)' or 'escitalopram+placebo' groups. We define the primary outcome as changes in the 17-item Hamilton Depression Rating Scale (HAMD-17). The secondary outcome is defined as changes in anti-inflammatory effects, cognitive function and quality of life.

Discussion: This study might be the first randomised, placebo-controlled trial to target at the PKC signal pathway in patients with TRD. Our study might help to propose individualised treatment strategies for depression.

Trial registration number: The trial protocol is registered with ClinicalTrials.gov under protocol ID 81930033 and ClinicalTrials.gov ID NCT04156425.

Keywords: depression; depressive disorder; treatment-resistant.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Protein kinase C (PKC) signalling pathway during the immune–inflammatory pathogenesis of TRD. Resting microglia could be activated into two subtypes: pro-inflammatory M1 microglia and anti-inflammatory M2 microglia. Maintaining a balanced state for the M1/M2 microglia is important for maintaining normal immunity in the CNS. Abnormal communication between microglia and neurons might lead to neuronal apoptosis, cognitive dysfunction and TRD. CNS, central nervous system; TRD, treatment-resistant depression.
Figure 2
Figure 2
Trial flowchart. We plan to recruit 180 patients with TRD and 60 healthy controls. For the patients who do not receive escitalopram or who received escitalopram at less than 20 mg/d, the patients will be randomised (1:1:1) into one of the following three groups: ‘escitalopram+golimumab’, ‘escitalopram+calcium tablet 500 mg/d+vitamin D 800 IU/d’ or ‘escitalopram+placebo’ groups. Primary and secondary study parameters will be accessed at baseline (week 0) and the 12th week. CA, calcium; ESC, escitalopram; Inflix, infliximab; TRD, treatment-resistant depression.

References

    1. Wickham S, Bentley L, Rose T, et al. . Effects on mental health of a UK welfare reform, universal credit: a longitudinal controlled study. Lancet Public Health 2020;5:e157–64. 10.1016/S2468-2667(20)30026-8
    1. Duman RS, Aghajanian GK, Sanacora G, et al. . Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 2016;22:238–49. 10.1038/nm.4050
    1. Somani A, Kar SK. Efficacy of repetitive transcranial magnetic stimulation in treatment-resistant depression: the evidence thus far. Gen Psychiatr 2019;32:e100074. 10.1136/gpsych-2019-100074
    1. Jha MK, Minhajuddin A, Gadad BS, et al. . Interleukin 17 selectively predicts better outcomes with bupropion-SSRI combination: novel T cell biomarker for antidepressant medication selection. Brain Behav Immun 2017;66:103–10. 10.1016/j.bbi.2017.07.005
    1. Ma K, Zhang H, Baloch Z. Pathogenetic and therapeutic applications of tumor necrosis factor-α (TNF-α) in major depressive disorder: a systematic review. Int J Mol Sci 2016;17:733. 10.3390/ijms17050733
    1. Bekhbat M, Chu K, Le N-A, et al. . Glucose and lipid-related biomarkers and the antidepressant response to infliximab in patients with treatment-resistant depression. Psychoneuroendocrinology 2018;98:222–9. 10.1016/j.psyneuen.2018.09.004
    1. Tang Y, Le W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 2016;53:1181–94. 10.1007/s12035-014-9070-5
    1. Attwells S, Setiawan E, Wilson AA, et al. . Replicating predictive serum correlates of greater translocator protein distribution volume in brain. Neuropsychopharmacology 2020;45:925–31. 10.1038/s41386-019-0561-y
    1. Liu Y, Zhang T, Meng D, et al. . Involvement of CX3CL1/CX3CR1 in depression and cognitive impairment induced by chronic unpredictable stress and relevant underlying mechanism. Behav Brain Res 2020;381:112371. 10.1016/j.bbr.2019.112371
    1. Guo X, Rao Y, Mao R, et al. . Common cellular and molecular mechanisms and interactions between microglial activation and aberrant neuroplasticity in depression. Neuropharmacology 2020;181:108336. 10.1016/j.neuropharm.2020.108336
    1. Zhang L, Zhang J, You Z. Switching of the microglial activation phenotype is a possible treatment for depression disorder. Front Cell Neurosci 2018;12:306. 10.3389/fncel.2018.00306
    1. Hong S, Beja-Glasser VF, Nfonoyim BM, et al. . Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 2016;352:712–6. 10.1126/science.aad8373
    1. Shi D-D, Huang Y-H, Lai CSW, et al. . Ginsenoside Rg1 prevents chemotherapy-induced cognitive impairment: associations with microglia-mediated cytokines, neuroinflammation, and neuroplasticity. Mol Neurobiol 2019;56:5626–42. 10.1007/s12035-019-1474-9
    1. Strawbridge R, Hodsoll J, Powell TR, et al. . Inflammatory profiles of severe treatment-resistant depression. J Affect Disord 2019;246:42–51. 10.1016/j.jad.2018.12.037
    1. van der Vorst EPC, Theodorou K, Wu Y, et al. . High-density lipoproteins exert pro-inflammatory effects on macrophages via passive cholesterol depletion and PKC-NF-κB/STAT1-IRF1 signaling. Cell Metab 2017;25:197–207. 10.1016/j.cmet.2016.10.013
    1. Mohanraj M, Sekar P, Liou H-H, et al. . The mycobacterial adjuvant analogue TDB attenuates neuroinflammation via Mincle-independent PLC-γ1/PKC/ERK signaling and microglial polarization. Mol Neurobiol 2019;56:1167–87. 10.1007/s12035-018-1135-4
    1. Guo X, Li Z, Zhang C, et al. . Down-regulation of PRKCB1 expression in Han Chinese patients with subsyndromal symptomatic depression. J Psychiatr Res 2015;69:1–6. 10.1016/j.jpsychires.2015.07.011
    1. Hu L, Zhang S, Wen H, et al. . Melatonin decreases M1 polarization via attenuating mitochondrial oxidative damage depending on UCP2 pathway in prorenin-treated microglia. PLoS One 2019;14:e0212138. 10.1371/journal.pone.0212138
    1. Zhou H, Jang H, Fleischmann RM, et al. . Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody, in subjects with rheumatoid arthritis. J Clin Pharmacol 2007;47:383–96. 10.1177/0091270006298188
    1. Khoraminya N, Tehrani-Doost M, Jazayeri S, et al. . Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Aust N Z J Psychiatry 2013;47:271–5. 10.1177/0004867412465022
    1. Li X, Tian X, Lv L, et al. . Microglia activation in the offspring of prenatal poly I: C exposed rats: a PET imaging and immunohistochemistry study. Gen Psychiatr 2018;31:e000006. 10.1136/gpsych-2018-000006
    1. Bertone-Johnson ER, Powers SI, Spangler L, et al. . Vitamin D supplementation and depression in the Women's Health Initiative calcium and vitamin D trial. Am J Epidemiol 2012;176:1–13. 10.1093/aje/kwr482
    1. Jorde R, Sneve M, Figenschau Y, et al. . Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med 2008;264:599–609. 10.1111/j.1365-2796.2008.02008.x
    1. Haddad Kashani H, Seyed Hosseini E, Nikzad H, et al. . The effects of vitamin D supplementation on signaling pathway of inflammation and oxidative stress in diabetic hemodialysis: a randomized, double-blind, placebo-controlled trial. Front Pharmacol 2018;9:50. 10.3389/fphar.2018.00050
    1. Şahin TD, Karson A, Balcı F, et al. . Tnf-Alpha inhibition prevents cognitive decline and maintains hippocampal BDNF levels in the unpredictable chronic mild stress rat model of depression. Behav Brain Res 2015;292:233–40. 10.1016/j.bbr.2015.05.062
    1. Derzi M, Johnson TR, Shoieb AM, et al. . Nonclinical evaluation of PF-06438179: a potential biosimilar to Remicade® (infliximab). Adv Ther 2016;33:1964–82. 10.1007/s12325-016-0403-9
    1. Tanaka Y, Harigai M, Takeuchi T, et al. . Clinical efficacy, radiographic progression, and safety through 156 weeks of therapy with subcutaneous golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate therapy: final results of the randomized GO-FORTH trial. Mod Rheumatol 2016;26:481–90. 10.3109/14397595.2015.1109762
    1. Guo X, Fu Y, Xu Y, et al. . Chronic mild restraint stress rats decreased CMKLR1 expression in distinct brain region. Neurosci Lett 2012;524:25–9. 10.1016/j.neulet.2012.06.075
    1. Wang Y, Huang Y, Xu Y, et al. . A dual AMPK/Nrf2 activator reduces brain inflammation after stroke by enhancing microglia M2 polarization. Antioxid Redox Signal 2018;28:141–63. 10.1089/ars.2017.7003

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel