Bipolar Disorder Integrative Staging: Incorporating Biomarkers Into Progression Across Stages

NCT07343739 | Active Not Recruiting

• 1 other identifier: PNRR-MAD-2022-12376693
• Study Type: observational
• Target: 126
• Locations: 1 country
• Sites: 1

Brief Summary

Bipolar disorder (BD) is a lifelong, recurrent condition with growing evidence supporting a neuroprogressive course, entailing the need to adopt staging models to guide stage-speci c interventions. Although different approaches have been proposed, their application remains limited and largely based on clinical features. BOARDING-PASS is an Italian government-funded, multicenter, prospective, and observational study aimed at advancing current knowledge of BD progression through the integration of clinical, biological, neuroimaging data, alongside machine learning (ML) methodologies. The study will enroll 120 subjects (age 18-70 years), classified according to the Kupka \& Hillegers' staging model, and recruited from three secondary-level psychiatric services in Italy. The primary outcome is the longitudinal assessment of clinical stage progression over an 18-month period, with evaluations conducted at baseline (T0), T1 (6 months), T2 (12 months), and T3 (18 months after baseline). At each time point, clinical variables will be collected, as well as clinical stages assigned. Additionally, at T0, T2, and T3, peripheral blood and unstimulated saliva samples will be collected to assess epigenetic regulation of gene expression - including DNA methylation, histone modi cations, and exosomal miRNAs - with a focus on key biomarkers such as C-reactive protein, proinflammatory cytokines, and BDNF, as well as microbial signatures of major oral bacterial phyla. Structural and resting state functional MRI scans will also be acquired at the same time points:structural data will be used to compute the structural connectome based on gyrification-based covariance networks, while resting-state data will be used to assess functional connectome alterations via graph theory metrics. Finally, all multimodal data will be integrated within a supervised ML algorithm based on Support Vector Machine, with the goal of developing a re ned, data-driven staging model for BD. BOARDING PASS project aligns with the growing need for a standardized, biologically informed staging framework that integrates clinical, inflammatory, epigenetic, and neuroimaging pro les to enhance prognostic accuracy and support tailored therapeutic interventions in BD.

Conditions

Bipolar Disorder

Keywords

bipolar disorder, neuroprogression, staging models, epigenetic, in learning, biomarkers, neuroimaging

Outcome Measures

Primary Outcomes (1)

• Clinical stage progression in Bipolar disorder

  The primary outcome of the BOARDING PASS study is the longitudinal assessment of clinical stage progression in BD at 6, 12, and 18 months, according to the Kupka \& Hillegers' staging model.

  18 months

Secondary Outcomes (1)

• Evaluation of biological and neuroimaging characteristics throughout the course of illness, along with their predictive power on illness progression.

  18 months

Other Outcomes (1)

• Machine learning algorithms

  18 months

Study Arms (1)

bipolar spectrum disorder

Subjects with a variety of manifestations of the bipolar spectrum, from having a first-degree relative with BD to a clinical diagnosis of full-blown BD according to the Kupka \& Hillegers' staging model.

Diagnostic Test: psychometric clinical assessment; Genetic: biological acquisition; Other: neuroimaging data

Interventions

psychometric clinical assessment DIAGNOSTIC_TEST

Clinical assessment will further include the administration of psychometric scales and questionnaires focused on clinical status, childhood trauma experiences, cognitive profile and adherence pattern

bipolar spectrum disorder

biological acquisition GENETIC

Biological samples for gene expression, inflammation, and microbiome analyses will be collected at baseline, T2 and T3.

bipolar spectrum disorder

neuroimaging data OTHER

MRI assessments will be performed using 3T scanners at T0, T2, and T3

bipolar spectrum disorder

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Subjects affected and unaffected by BD whose clinical stage falls within those defined by the Kupka and Hillegers model, namely: stage 0 (increased risk: having a first-degree relative with BD, in the absence of psychiatric symptoms); stage 1 (having a first-degree relative with BD, in the presence of non-specific psychiatric symptoms or depressive episode(s)); stage 2 (first hypo/manic episode allowing a diagnosis of BD type I or II according to DSM-5; APA, 2013); stage 3 (recurrent episode(s): depressive, hypo/manic, or mixed); stage 4 (persistent non-remitting disorder: chronic depressive, manic, or mixed episodes, including rapid cycling);

You may qualify if:

• A range of bipolar spectrum manifestations meeting the criteria of the Kupka \& Hillegers' staging model
• Both genders
• Age ≥18 and ≤70 years
• Written informed consent obtained

You may not qualify if:

• Inability to provide informed consent
• Diagnosis of intellectual disability
• Presence of a severe medical condition (e.g., previously diagnosed neurological disorders, including chronic migraine, hematological diseases, renal disorders, history of stroke, or diabetes mellitus, even if compensated; controlled hypertension allowed)
• Current substance use disorder or within six months prior to screening

Sponsors & Collaborators

• ASST Fatebenefratelli Sacco: lead

Study Sites (1)

ASST Fatebenefratelli Sacco

Milan, Italy

Location

Related Publications (10)

• van der Markt A, Klumpers UM, Draisma S, Dols A, Nolen WA, Post RM, Altshuler LL, Frye MA, Grunze H, Keck PE Jr, McElroy SL, Suppes T, Beekman AT, Kupka RW. Testing a clinical staging model for bipolar disorder using longitudinal life chart data. Bipolar Disord. 2019 May;21(3):228-234. doi: 10.1111/bdi.12727. Epub 2018 Dec 12.

  PMID: 30447123 RESULT

• Di Francesco A, Arosio B, Falconi A, Micioni Di Bonaventura MV, Karimi M, Mari D, Casati M, Maccarrone M, D'Addario C. Global changes in DNA methylation in Alzheimer's disease peripheral blood mononuclear cells. Brain Behav Immun. 2015 Mar;45:139-44. doi: 10.1016/j.bbi.2014.11.002. Epub 2014 Nov 13.

  PMID: 25452147 RESULT

• D'Addario C, Dell'Osso B, Galimberti D, Palazzo MC, Benatti B, Di Francesco A, Scarpini E, Altamura AC, Maccarrone M. Epigenetic modulation of BDNF gene in patients with major depressive disorder. Biol Psychiatry. 2013 Jan 15;73(2):e6-7. doi: 10.1016/j.biopsych.2012.07.009. Epub 2012 Aug 14. No abstract available.

  PMID: 22901293 RESULT

• D'Addario C, Dell'Osso B, Palazzo MC, Benatti B, Lietti L, Cattaneo E, Galimberti D, Fenoglio C, Cortini F, Scarpini E, Arosio B, Di Francesco A, Di Benedetto M, Romualdi P, Candeletti S, Mari D, Bergamaschini L, Bresolin N, Maccarrone M, Altamura AC. Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII. Neuropsychopharmacology. 2012 Jun;37(7):1647-55. doi: 10.1038/npp.2012.10. Epub 2012 Feb 22.

  PMID: 22353757 RESULT

• Berk M, Berk L, Dodd S, Cotton S, Macneil C, Daglas R, Conus P, Bechdolf A, Moylan S, Malhi GS. Stage managing bipolar disorder. Bipolar Disord. 2014 Aug;16(5):471-7. doi: 10.1111/bdi.12099. Epub 2013 Jun 20.

  PMID: 23782499 RESULT

• Martella F, Caporali A, Macellaro M, Cafaro R, De Pasquale F, Dell'Osso B, D'Addario C. Biomarker identification in bipolar disorder. Pharmacol Ther. 2025 Apr;268:108823. doi: 10.1016/j.pharmthera.2025.108823. Epub 2025 Feb 17.

  PMID: 39965667 RESULT

• Girella A, Vismara M, O'Riordan KJ, Gunnigle E, Mercante F, Girone N, Pucci M, Gatta V, Konstantinidou F, Stuppia L, Cryan JF, Dell'Osso B, D'Addario C. New Insights into the oral microbiota and host epigenetic changes in obsessive compulsive disorder and major depressive disorder: Focus on BDNF. Pharmacol Res. 2025 Sep;219:107891. doi: 10.1016/j.phrs.2025.107891. Epub 2025 Jul 30.

  PMID: 40749756 RESULT

• Dell'Osso B, Cremaschi L, Macellaro M, Cafaro R, Girone N. Bipolar disorder staging and the impact it has on its management: an update. Expert Rev Neurother. 2024 Jun;24(6):565-574. doi: 10.1080/14737175.2024.2355264. Epub 2024 May 16.

  PMID: 38753491 RESULT

• Macellaro M, Girone N, Cremaschi L, Bosi M, Cesana BM, Ambrogi F, Caricasole V, Giorgetti F, Ketter TA, Dell'Osso B. Staging models applied in a sample of patients with bipolar disorder: Results from a retrospective cohort study. J Affect Disord. 2023 Feb 15;323:452-460. doi: 10.1016/j.jad.2022.11.081. Epub 2022 Nov 28.

  PMID: 36455717 RESULT

• Cremaschi L, Macellaro M, Girone N, Bosi M, Cesana BM, Ambrogi F, Dell'Osso B. The progression trajectory of Bipolar Disorder: results from the application of a staging model over a ten-year observation. J Affect Disord. 2024 Oct 1;362:186-193. doi: 10.1016/j.jad.2024.06.094. Epub 2024 Jun 27.

  PMID: 38944295 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Biological samples for gene expression, inflammation, and microbiome analyses will be collected at baseline, T2 and T3. Specifically: 1. unstimulated saliva samples -i.e., whole saliva collected under resting conditions without gustatory, masticatory, or pharmacological stimulation- will be obtained using cotton buccal swabs (Salivette, Sarstedt, Nümbrecht, Germany) and stored at -20 °C until genomic DNA (gDNA) extraction. Exosomes wil be also isolated from saliva and miRNAs purified using an exosome RNA isolation kit. 2. peripheral venous blood samples will be collected in two 5 ml vacutainer tubes containing sodium citrate. Serum and cellular components will be separated and total RNA as well as gDNA will be extracted from PBMCs.

MeSH Terms

Conditions

Bipolar Disorder

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mood Disorders; Mental Disorders

Study Officials

• Bernardo Maria Dell'Osso

  ASST Fatebenefratelli Sacco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 18 Months
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 7, 2026
• First Posted: January 15, 2026
• Study Start: November 8, 2023
• Primary Completion (Estimated): May 20, 2026
• Study Completion (Estimated): May 20, 2026
• Last Updated: January 15, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)