Validation of the predictive value of BDNF -87 methylation for antidepressant treatment success in severely depressed patients-a randomized rater-blinded trial.
BDNF
Biomarker
Major depressive disorder
RCT
Journal
Trials
ISSN: 1745-6215
Titre abrégé: Trials
Pays: England
ID NLM: 101263253
Informations de publication
Date de publication:
09 Apr 2024
09 Apr 2024
Historique:
received:
24
11
2023
accepted:
18
03
2024
medline:
10
4
2024
pubmed:
10
4
2024
entrez:
9
4
2024
Statut:
epublish
Résumé
Brain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE). The BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study's main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE. The trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals. German Clinical Trial Register DRKS00032503. Registered on 17 August 2023.
Sections du résumé
BACKGROUND
BACKGROUND
Brain-derived neurotrophic factor (BDNF) is essential for antidepressant treatment of major depressive disorder (MDD). Our repeated studies suggest that DNA methylation of a specific CpG site in the promoter region of exon IV of the BDNF gene (CpG -87) might be predictive of the efficacy of monoaminergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others. This trial aims to evaluate whether knowing the biomarker is non-inferior to treatment-as-usual (TAU) regarding remission rates while exhibiting significantly fewer adverse events (AE).
METHODS
METHODS
The BDNF trial is a prospective, randomized, rater-blinded diagnostic study conducted at five university hospitals in Germany. The study's main hypothesis is that {1} knowing the methylation status of CpG -87 is non-inferior to not knowing it with respect to the remission rate while it significantly reduces the AE rate in patients experiencing at least one AE. The baseline assessment will occur upon hospitalization and a follow-up assessment on day 49 (± 3). A telephone follow-up will be conducted on day 70 (± 3). A total of 256 patients will be recruited, and methylation will be evaluated in all participants. They will be randomly assigned to either the marker or the TAU group. In the marker group, the methylation results will be shared with both the patient and their treating physician. In the TAU group, neither the patients nor their treating physicians will receive the marker status. The primary endpoints include the rate of patients achieving remission on day 49 (± 3), defined as a score of ≤ 10 on the Hamilton Depression Rating Scale (HDRS-24), and the occurrence of AE.
ETHICS AND DISSEMINATION
BACKGROUND
The trial protocol has received approval from the Institutional Review Boards at the five participating universities. This trial holds significance in generating valuable data on a predictive biomarker for antidepressant treatment in patients with MDD. The findings will be shared with study participants, disseminated through professional society meetings, and published in peer-reviewed journals.
TRIAL REGISTRATION
BACKGROUND
German Clinical Trial Register DRKS00032503. Registered on 17 August 2023.
Identifiants
pubmed: 38594753
doi: 10.1186/s13063-024-08061-5
pii: 10.1186/s13063-024-08061-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
247Subventions
Organisme : Bundesministerium für Bildung und Forschung
ID : 01EK2204A
Informations de copyright
© 2024. The Author(s).
Références
Bundesärztekammer (BÄK), Kassenärztliche Bundesvereinigung (KBV), Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Nationale VersorgungsLeitlinie Unipolare Depression – Langfassung, Version 3.1. 2022. 2022.
National Institute for Health and Care Excellence. Depression in adults: treatment and management: NICE guideline short version. 2018 May.
Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments Can J Psychiatry. 2016;61(9):540–60.
doi: 10.1177/0706743716659417
pubmed: 27486148
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–17.
doi: 10.1176/ajp.2006.163.11.1905
pubmed: 17074942
McAllister-Williams RH, Arango C, Blier P, Demyttenaere K, Falkai P, Gorwood P, et al. The identification, assessment and management of difficult-to-treat depression: an international consensus statement. J Affect Disord. 2020;15(267):264–82.
doi: 10.1016/j.jad.2020.02.023
Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, et al. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev. 2021;9(9):CD011612.
pubmed: 34510411
Rhee TG, Shim SR, Forester BP, Nierenberg AA, McIntyre RS, Papakostas GI, et al. Efficacy and safety of ketamine vs electroconvulsive therapy among patients with major depressive episode: a systematic review and meta-analysis. JAMA Psychiat. 2022;79(12):1162–72.
doi: 10.1001/jamapsychiatry.2022.3352
Mrazek DA, Hornberger JC, Altar CA, Degtiar I. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996–2013. Psychiatr Serv. 2014;65(8):977–87.
doi: 10.1176/appi.ps.201300059
pubmed: 24789696
Nemeroff CB, Mayberg HS, Krahl SE, McNamara J, Frazer A, Henry TR, et al. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology. 2006;31(7):1345–55.
doi: 10.1038/sj.npp.1301082
pubmed: 16641939
Arns M, van Dijk H, Luykx JJ, van Wingen G, Olbrich S. Stratified psychiatry: tomorrow’s precision psychiatry? Eur Neuropsychopharmacol. 2022;55:14–9.
doi: 10.1016/j.euroneuro.2021.10.863
pubmed: 34768212
Serretti A. Precision psychiatry. Braz J Psychiatry. 2022;44(2):115–6.
doi: 10.1590/1516-4446-2021-1997
pubmed: 34190828
Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455(7215):894–902.
doi: 10.1038/nature07455
pubmed: 18923511
pmcid: 2721780
Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry. 2008;64(6):527–32.
doi: 10.1016/j.biopsych.2008.05.005
pubmed: 18571629
pmcid: 2597158
Brunoni AR, Lopes M, Fregni F. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol. 2008;11(8):1169–80.
doi: 10.1017/S1461145708009309
pubmed: 18752720
Molendijk ML, Bus BAA, Spinhoven P, Penninx BWJH, Kenis G, Prickaerts J, et al. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Mol Psychiatry. 2011;16(11):1088–95.
doi: 10.1038/mp.2010.98
pubmed: 20856249
Cattaneo A, Cattane N, Begni V, Pariante CM, Riva MA. The human BDNF gene: peripheral gene expression and protein levels as biomarkers for psychiatric disorders. Transl Psychiatry. 2016;6(11): e958.
doi: 10.1038/tp.2016.214
pubmed: 27874848
pmcid: 5314126
Tadić A, Müller-Engling L, Schlicht KF, Kotsiari A, Dreimüller N, Kleimann A, et al. Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression. Mol Psychiatry. 2014;19(3):281–3.
doi: 10.1038/mp.2013.58
pubmed: 23670489
Lieb K, Dreimüller N, Wagner S, Schlicht K, Falter T, Neyazi A, et al. BDNF Plasma Levels and BDNF Exon IV Promoter Methylation as Predictors for Antidepressant Treatment Response. Front Psychiatry. 2018;26(9):511.
doi: 10.3389/fpsyt.2018.00511
Pathak H, Borchert A, Garaali S, Burkert A, Frieling H. BDNF exon IV promoter methylation and antidepressant action: a complex interplay. Clin Epigenetics. 2022;14(1):187–93.
doi: 10.1186/s13148-022-01415-3
pubmed: 36572893
pmcid: 9793565
Wang P, Zhang C, Lv Q, Bao C, Sun H, Ma G, et al. Association of DNA methylation in BDNF with escitalopram treatment response in depressed Chinese Han patients. Eur J Clin Pharmacol. 2018;74(8):1011–20.
doi: 10.1007/s00228-018-2463-z
pubmed: 29748862
Barth M, Kriston L, Klostermann S, Barbui C, Cipriani A, Linde K. Efficacy of selective serotonin reuptake inhibitors and adverse events: meta-regression and mediation analysis of placebo-controlled trials. Br J Psychiatry. 2016;208(2):114–9.
doi: 10.1192/bjp.bp.114.150136
pubmed: 26834168
Fava M, Rush AJ, Alpert JE, Balasubramani GK, Wisniewski SR, Carmin CN, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165(3):342–51.
doi: 10.1176/appi.ajp.2007.06111868
pubmed: 18172020
Tiller JWG. Depression and anxiety. Med J Aust. 2013;199(S6):28.
doi: 10.5694/mja12.10628
Demyttenaere K, Heirman E. The blurred line between anxiety and depression: hesitations on comorbidity, thresholds and hierarchy. Int Rev Psychiatry. 2020;32(5–6):455–65.
doi: 10.1080/09540261.2020.1764509
pubmed: 32436448