Blocking CCR5 activity by maraviroc augmentation in post-stroke depression: a proof-of-concept clinical trial.
CCR5 antagonist
Clinical trial
Drug repurposing
Maraviroc
Post-stroke depression (PSD)
Journal
BMC neurology
ISSN: 1471-2377
Titre abrégé: BMC Neurol
Pays: England
ID NLM: 100968555
Informations de publication
Date de publication:
06 Jun 2024
06 Jun 2024
Historique:
received:
16
10
2023
accepted:
20
05
2024
medline:
7
6
2024
pubmed:
7
6
2024
entrez:
6
6
2024
Statut:
epublish
Résumé
Post-stroke depression (PSD) is a significant impediment to successful rehabilitation and recovery after a stroke. Current therapeutic options are limited, leaving an unmet demand for specific and effective therapeutic options. Our objective was to investigate the safety of Maraviroc, a CCR5 antagonist, as a possible mechanism-based add-on therapeutic option for PSD in an open-label proof-of-concept clinical trial. We conducted a 10-week clinical trial in which ten patients with subcortical and cortical stroke, suffering from PSD. were administered a daily oral dose of 300 mg Maraviroc. Participants were then monitored for an additional eight weeks. The primary outcome measure was serious treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. The secondary outcome measure was a change in the Montgomery-Asberg Depression Rating Scale (MADRS). Maraviroc was well tolerated, with no reports of serious adverse events or discontinuations due to intolerance. The MADRS scores substantially reduced from baseline to week 10 (mean change: -16.4 ± 9.3; p < 0.001). By the conclusion of the treatment phase, a favorable response was observed in five patients, with four achieving remission. The time to response was relatively short, approximately three weeks. After the cessation of treatment, MADRS scores increased at week 18 by 6.1 ± 9.6 points (p = 0.014). Our proof-of-concept study suggests that a daily dosage of 300 mg of Maraviroc may represent a well-tolerated and potentially effective pharmacological approach to treating PSD. Further comprehensive placebo-controlled studies are needed to assess the impact of Maraviroc augmentation on PSD. ClinicalTrials.gov Identifier: NCT05932550, Retrospectively registered: 28/06/2023.
Sections du résumé
BACKGROUND
BACKGROUND
Post-stroke depression (PSD) is a significant impediment to successful rehabilitation and recovery after a stroke. Current therapeutic options are limited, leaving an unmet demand for specific and effective therapeutic options. Our objective was to investigate the safety of Maraviroc, a CCR5 antagonist, as a possible mechanism-based add-on therapeutic option for PSD in an open-label proof-of-concept clinical trial.
METHODS
METHODS
We conducted a 10-week clinical trial in which ten patients with subcortical and cortical stroke, suffering from PSD. were administered a daily oral dose of 300 mg Maraviroc. Participants were then monitored for an additional eight weeks. The primary outcome measure was serious treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. The secondary outcome measure was a change in the Montgomery-Asberg Depression Rating Scale (MADRS).
RESULTS
RESULTS
Maraviroc was well tolerated, with no reports of serious adverse events or discontinuations due to intolerance. The MADRS scores substantially reduced from baseline to week 10 (mean change: -16.4 ± 9.3; p < 0.001). By the conclusion of the treatment phase, a favorable response was observed in five patients, with four achieving remission. The time to response was relatively short, approximately three weeks. After the cessation of treatment, MADRS scores increased at week 18 by 6.1 ± 9.6 points (p = 0.014).
CONCLUSIONS
CONCLUSIONS
Our proof-of-concept study suggests that a daily dosage of 300 mg of Maraviroc may represent a well-tolerated and potentially effective pharmacological approach to treating PSD. Further comprehensive placebo-controlled studies are needed to assess the impact of Maraviroc augmentation on PSD.
TRIAL REGISTRATION
BACKGROUND
ClinicalTrials.gov Identifier: NCT05932550, Retrospectively registered: 28/06/2023.
Identifiants
pubmed: 38844862
doi: 10.1186/s12883-024-03683-3
pii: 10.1186/s12883-024-03683-3
doi:
Substances chimiques
Maraviroc
MD6P741W8A
CCR5 Receptor Antagonists
0
CCR5 protein, human
0
Triazoles
0
Receptors, CCR5
0
Banques de données
ClinicalTrials.gov
['NCT05932550']
Types de publication
Journal Article
Clinical Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
190Informations de copyright
© 2024. The Author(s).
Références
Broomfield NM, Quinn TJ, Abdul-Rahim AH, Walters MR, Evans JJ. Depression and anxiety symptoms post-stroke/TIA: prevalence and associations in cross-sectional data from a regional stroke registry. BMC Neurol. 2014;14(1). https://doi.org/10.1186/S12883-014-0198-8 .
Ayerbe L, Ayis S, Wolfe CDA, Rudd AG. Natural history, predictors and outcomes of depression after stroke: systematic review and meta-analysis. Br J Psychiatry. 2013;202(1):14–21. https://doi.org/10.1192/BJP.BP.111.107664 .
doi: 10.1192/BJP.BP.111.107664
pubmed: 23284148
Tene O, Shenhar-Tsarfaty S, Korczyn AD, Kliper E, Hallevi H, Shopin L, Auriel E, Mike A, Bornstein NM, Assayag EB. Depressive symptoms following stroke and transient ischemic attack: is it time for a more intensive treatment approach? Results from the TABASCO cohort study. J Clin Psychiatry. 2016;77(5):673–80. https://doi.org/10.4088/JCP.14M09759 .
doi: 10.4088/JCP.14M09759
pubmed: 27035632
Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, Kubera M, Bob P, Lerer B, Maj M. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis. 2009;24(1):27–53. https://doi.org/10.1007/S11011-008-9118-1 .
doi: 10.1007/S11011-008-9118-1
pubmed: 19085093
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238–49. https://doi.org/10.1038/NM.4050 .
doi: 10.1038/NM.4050
pubmed: 26937618
pmcid: 5405628
Pawluk H, Woźniak A, Grześk G, Kołodziejska R, Kozakiewicz M, Kopkowska E, Grzechowiak E, Kozera G. The role of selected pro-inflammatory cytokines in Pathogenesis of ischemic stroke. Clin Interv Aging. 2020;15:469–84. https://doi.org/10.2147/CIA.S233909 .
doi: 10.2147/CIA.S233909
pubmed: 32273689
pmcid: 7110925
Kim YK, Na KS, Myint AM, Leonard BE. The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:277–84. https://doi.org/10.1016/J.PNPBP.2015.06.008 .
doi: 10.1016/J.PNPBP.2015.06.008
pubmed: 26111720
Sorce S, Myburgh R, Krause KH. The chemokine receptor CCR5 in the central nervous system. Prog Neurobiol. 2011;93(2):297–311. https://doi.org/10.1016/J.PNEUROBIO.2010.12.003 .
doi: 10.1016/J.PNEUROBIO.2010.12.003
pubmed: 21163326
Zhou M, Greenhill S, Huang S, Silva TK, Sano Y, Wu S, Cai Y, Nagaoka Y, Sehgal M, Cai DJ, Lee YS, Fox K, Silva AJ. CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory. Elife. 2016;5(DECEMBER2016). https://doi.org/10.7554/ELIFE.20985 .
Joy MT, Ben Assayag E, Shabashov-Stone D, Liraz-Zaltsman S, Mazzitelli J, Arenas M, Abduljawad N, Kliper E, Korczyn AD, Thareja NS, Kesner EL, Zhou M, Huang S, Silva TK, Katz N, Bornstein NM, Silva AJ, Shohami E, Carmichael ST. CCR5 is a therapeutic target for recovery after stroke and traumatic brain Injury. Cell. 2019;176(5):1143–e115713. https://doi.org/10.1016/J.CELL.2019.01.044 .
doi: 10.1016/J.CELL.2019.01.044
pubmed: 30794775
pmcid: 7259116
Tene O, Hallevi H, Molad J, Usher S, Seyman E, Bornstein NM, Shenhar-Tsarfaty S, Ben Assayag E. CCR5-∆32 polymorphism: a possible protective factor for post-stroke depressive symptoms. J Psychiatry Neurosci. 2021;46(4):E431–40. https://doi.org/10.1503/JPN.200197 .
doi: 10.1503/JPN.200197
pubmed: 34291627
pmcid: 8519488
Abel S, Back DJ, Vourvahis M. Maraviroc: pharmacokinetics and drug interactions. Antivir Ther. 2009;14(5):607–18. https://doi.org/10.1177/135965350901400514 .
doi: 10.1177/135965350901400514
pubmed: 19704163
Parra J, Portilla J, Pulido F, Sãnchez-De La Rosa R, Alonso-Villaverde C, Berenguer J, Blanco JL, Domingo P, Dronda F, Galera C, Gutirrez F, Kindeln JM, Knobel H, Leal M, Lpez-Aldeguer J, Mario A, Miralles C, Molt J, Ortega E, Oteo JA. Clinical utility of maraviroc. Clin Drug Investig. 2011;31(8):527–42. https://doi.org/10.2165/11590700-000000000-00000 .
doi: 10.2165/11590700-000000000-00000
pubmed: 21595497
Garcia-Perez J, Rueda P, Staropoli I, Kellenberger E, Alcami J, Arenzana-Seisdedos F, Lagane B. New insights into the mechanisms whereby low molecular weight CCR5 ligands inhibit HIV-1 infection. J Biol Chem. 2011;286(7):4978–90. https://doi.org/10.1074/JBC.M110.168955 .
doi: 10.1074/JBC.M110.168955
pubmed: 21118814
Fernández I, de Lazzari E, Inciarte A, Diaz-Brito V, Milinkovic A, Arenas-Pinto A, Etcheverrry F, García F, Leal L, Fernandez E, Gonzalez E, Lucero C, Leon A, Garcıa F, Manzardo C, Nicolas D, Bodro M, del Rıo A, Cardozo C, Cervera C, Pericas JM, Sanclemente G, de la Calle C, Morata L, Soriano A, Espinosa G, Blanco J, ́L, Martınez E, Mallolas J, Miró J, Laguno M, Rojas J, Martınez-Rebollar M, Gonzalez-Cordon A, Cervera C, Knobel H, Peraire J, Domingo P, Clotet B, Dalmau D, Cruceta A, Arnaiz JA, Gatell JM. Network meta-analysis of post-exposure prophylaxis randomized clinical trials. HIV Med. 2021;22(3):218–24. https://doi.org/10.1111/HIV.12964 .
doi: 10.1111/HIV.12964
pubmed: 33108035
American Psychiatric Association APA. 2013. Diagnostic and Statistical Manual of Mental Disorders (5th Ed.).; 2013.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134(4):382–9. https://doi.org/10.1192/bjp.134.4.382 .
doi: 10.1192/bjp.134.4.382
pubmed: 444788
Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB. The 16-item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54(5):573–83. https://doi.org/10.1016/S0006-3223(02)01866-8 .
doi: 10.1016/S0006-3223(02)01866-8
pubmed: 12946886
Guy W. CGI clinical global impressions. ECDEU Assess Man. Published online; 1976.
Spitzer RL, Kroenke K, Williams JBW, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092–7. https://doi.org/10.1001/ARCHINTE.166.10.1092 .
doi: 10.1001/ARCHINTE.166.10.1092
pubmed: 16717171
Ludbrook J. On making multiple comparisons in clinical and experimental pharmacology and physiology. Clin Exp Pharmacol Physiol. 1991;18(6):379–92. https://doi.org/10.1111/J.1440-1681.1991.TB01468.X .
doi: 10.1111/J.1440-1681.1991.TB01468.X
pubmed: 1914240
Molad J, Hallevi H, Seyman E, Rotschild O, Bornstein NM, Tene O, Giladi N, Hausdorff JM, Mirelman A, Ben Assayag E. CCR5-∆32 polymorphism-a possible protective factor from gait impairment amongst post-stroke patients. Eur J Neurol. 2023;30(3):692–701. https://doi.org/10.1111/ENE.15637 .
doi: 10.1111/ENE.15637
pubmed: 36380716
Ben Assayag E, Tene O, Korczyn AD, Shopin L, Auriel E, Molad J, Hallevi H, Kirschbaum C, Bornstein NM, Shenhar-Tsarfaty S, Kliper E, Stalder T. High hair cortisol concentrations predict worse cognitive outcome after stroke: results from the TABASCO prospective cohort study. Psychoneuroendocrinology. 2017;82:133–9. https://doi.org/10.1016/J.PSYNEUEN.2017.05.013 .
doi: 10.1016/J.PSYNEUEN.2017.05.013
pubmed: 28549269
Shenhar-Tsarfaty S, Assayag E, Ben, Bova I, Shopin L, Cohen M, Berliner S, Shapira I, Bornstein NM. Persistent hyperfibrinogenemia in acute ischemic stroke / transient ischemic attack (TIA). Thromb Haemost. 2008;99(1):169–73. https://doi.org/10.1160/TH07-08-0484 .
doi: 10.1160/TH07-08-0484
pubmed: 18217150
Miller AH. Norman Cousins Lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain Behav Immun. 2009;23(2):149–58. https://doi.org/10.1016/J.BBI.2008.08.006 .
doi: 10.1016/J.BBI.2008.08.006
pubmed: 18793712
O’Connor JC, André C, Wang Y, Lawson MA, Szegedi SS, Lestage J, Castanon N, Kelley KW, Dantzer R. Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci. 2009;29(13):4200–9. https://doi.org/10.1523/JNEUROSCI.5032-08.2009 .
doi: 10.1523/JNEUROSCI.5032-08.2009
pubmed: 19339614
pmcid: 2835569
Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R. The new 5-HT hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):702–21. https://doi.org/10.1016/J.PNPBP.2010.12.017 .
doi: 10.1016/J.PNPBP.2010.12.017
pubmed: 21185346
Starkstein SE, Robinson RG, Price TR. Comparison of cortical and subcortical lesions in the production of poststroke mood disorders. Brain. 1987;110(4):1045–59. https://doi.org/10.1093/BRAIN/110.4.1045 . (Pt 4).
doi: 10.1093/BRAIN/110.4.1045
pubmed: 3651794
Zhang T, Jing X, Zhao X, Wang C, Liu Z, Zhou Y, Wang Y, Wang Y. A prospective cohort study of lesion location and its relation to post-stroke depression among Chinese patients. J Affect Disord. 2012;136(1–2). https://doi.org/10.1016/J.JAD.2011.06.014 .
Yasuno F, Taguchi A, Yamamoto A, Kajimoto K, Kazui H, Kudo T, Kikuchi-Taura A, Sekiyama A, Kishimoto T, Iida H, Nagatsuka K. Microstructural abnormality in white matter, regulatory T lymphocytes, and depressive symptoms after stroke. Psychogeriatrics. 2014;14(4):213–21. https://doi.org/10.1111/PSYG.12084 .
doi: 10.1111/PSYG.12084
pubmed: 25495082
Pavlovic AM, Pekmezovic T, Zidverc Trajkovic J, Svabic Medjedovic T, Veselinovic N, Radojicic A, Mijajlovic M, Tomic G, Jovanovic Z, Norton M, Sternic N. Baseline characteristic of patients presenting with lacunar stroke and cerebral small vessel disease may predict future development of depression. Int J Geriatr Psychiatry. 2016;31(1):58–65. https://doi.org/10.1002/GPS.4289 .
doi: 10.1002/GPS.4289
pubmed: 25821003
Simpson S, Baldwin RC, Jackson A, Burns AS. Is subcortical disease associated with a poor response to antidepressants? Neurological, neuropsychological and neuroradiological findings in late-life depression. Psychol Med. 1998;28(5):1015–26. https://doi.org/10.1017/S003329179800693X .
doi: 10.1017/S003329179800693X
pubmed: 9794009
Patankar TF, Baldwin R, Mitra D, Jeffries S, Sutcliffe C, Burns A, Jackson A. Virchow-Robin space dilatation may predict resistance to antidepressant monotherapy in elderly patients with depression. J Affect Disord. 2007;97(1–3):265–70. https://doi.org/10.1016/J.JAD.2006.06.024 .
doi: 10.1016/J.JAD.2006.06.024
pubmed: 16919335
Chollet F, Tardy J, Albucher JF, Thalamas C, Berard E, Lamy C, Bejot Y, Deltour S, Jaillard A, Niclot P, Guillon B, Moulin T, Marque P, Pariente J, Arnaud C, Loubinoux I. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 2011;10(2):123–30. https://doi.org/10.1016/S1474-4422(10)70314-8 .
doi: 10.1016/S1474-4422(10)70314-8
pubmed: 21216670
Mondal S, Rangasamy SB, Roy A, Dasarathy S, Kordower JH, Pahan K. Low-Dose Maraviroc, an antiretroviral drug, attenuates the Infiltration of T Cells into the Central Nervous System and protects the Nigrostriatum in Hemiparkinsonian Monkeys. J Immunol. 2019;202(12):3412–22. https://doi.org/10.4049/JIMMUNOL.1800587 .
doi: 10.4049/JIMMUNOL.1800587
pubmed: 31043478
Piconi S, Foschi A, Malagoli A, Carli F, Zona S, Milic J, Ricci ED, Rizzardini G, Guaraldi G. Impact of prolonged maraviroc treatment on non-AIDS-related comorbidities in HIV-positive patients: a retrospective cohort study. J Antimicrob Chemother. 2019;74(9):2723–31. https://doi.org/10.1093/JAC/DKZ227 .
doi: 10.1093/JAC/DKZ227
pubmed: 31139818
Robinson RG, Jorge RE. Post-stroke Depression: a review. Am J Psychiatry. 2016;173(3):221–31. https://doi.org/10.1176/APPI.AJP.2015.15030363 .
doi: 10.1176/APPI.AJP.2015.15030363
pubmed: 26684921
Kantak SS, Stinear JW, Buch ER, Cohen LG. Rewiring the brain: potential role of the premotor cortex in motor control, learning, and recovery of function following brain injury. Neurorehabil Neural Repair. 2012;26(3):282–92. https://doi.org/10.1177/1545968311420845 .
doi: 10.1177/1545968311420845
pubmed: 21926382
Assayag EB, Molad J, Seyman E, Rotschild O, Zeltzer E, Sadeh-Gonik U, Bregman N, Alpernas A, Segal Y, Bashat DB, Nathan T, Hawwari M, Tene O, Hallevi H. Preventing post-stroke dementia. The MARCH Trial. Protocol and statistical analysis plan of a randomized clinical trial testing the safety and efficacy of Maraviroc in post-stroke cognitive impairment. Eur Stroke J. 2022;7(3):314–22. https://doi.org/10.1177/23969873221098857 .
doi: 10.1177/23969873221098857
pubmed: 36082248
pmcid: 9446318