Integrins and Protocadherins in Glutamatergic Circuits: Identification of Common Signaling Pathways and Molecular Targets in Anxiety and Major Depressive Disorders (GAPsy)

NCT06167590 | Unknown

• 1 other identifier: GAPsy
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this study is to identify biologically viable targets for the treatment of major depressive disorder (MDD) and anxiety disorder (AD) with the ultimate goal of guiding physicians' therapeutic strategies and identifying more effective and safer treatments for patients. Following the inclusion and exclusion criteria, the investigators will recruit 10 patients with a diagnosis of anxious-depressive disorder (MDD-AD) and 10 healthy controls (HC) subjects. Each participant will be evaluated by a team of expert psychologists and physicians, who will be conducting a structured interview and administering a set of psychopathological scales to assess the symptoms' severity. The participants will also undergo7T multimodal neuroimaging session (including T1-weighted, 1H-MRS and fMRI). In the second part of the study, murine models will be used to study the role of integrin β3 (Itgb3) and protocadherin 9 (Pcdh9) in glutamatergic transmission at a molecular level and to evaluate whether the electrophysiological and behavioral defects identified in Itgb3- and Pcdh9-knockout mice can be restored by CRISPR-mediated transcription activation (CRISPRa).

Conditions

Depression, Anxiety; Healthy

Keywords

Depression, Anxiety; Healthy controls; Neuroimaging; Functional magnetic resonance imaging (fMRI); Proton magnetic resonance spectroscopy (1H-MRS); Murine models; Integrin β3; Protocadherin 9; CRISPR-mediated transcription activation (CRISPRa)

Outcome Measures

Primary Outcomes (4)

• Brain structure differences in terms of white matter in the prefrontal-limbic pathway

  Evaluation of volumetric differences in terms of white matter in the prefrontal-limbic pathway, comparing the healthy controls group and the patients group, using structural neuroimaging (MRI)

  At T2 (third visit, within a month from the second visit)

• Brain structure differences in terms of gray matter in the prefrontal-limbic pathway

  Evaluation of volumetric differences in terms of white matter in the prefrontal-limbic pathway, comparing the healthy controls group and the patients group, using structural neuroimaging (MRI)

  At T2 (third visit, within a month from the second visit)

• Functional connectivity differences in the prefrontal-limbic pathway

  Evaluation of connectivity differences at rest and during task in the prefrontal-limbic pathway, comparing the healthy controls group and the patients group, using functional neuroimaging (fMRI)

  At T2 (third visit, within a month from the second visit)

• Differences in the glutamatergic neurotransmission in the anterior cingulate and prefrontal dorsolateral cortices as assessed by using 1H-MRS

  Evaluation of glutamatergic neurotransmission differences in the anterior cingulate and prefrontal dorsolateral cortices, comparing the healthy controls group and the patients group, using in vivo proton magnetic resonance spectroscopy (1H-MRS)

  At T2 (third visit, within a month from the second visit)

Study Arms (2)

Anxious-depressive disorder

OTHER

Diagnostic Test: GAPsy protocol

Healthy controls

OTHER

Diagnostic Test: GAPsy protocol

Interventions

GAPsy protocol DIAGNOSTIC_TEST

Each participant will undergo a 7 T multimodal neuroimaging session, including T1-weighted, 1H-MRS and fMRI. Each participant will also be assessed through a structured clinical interview (SCID-I e SCID-II) and will be administered scales such as HAM-A, HAM-D, BPRS and MADRS.

Anxious-depressive disorder; Healthy controls

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Patients group: diagnosis of anxiety-depressive disorder based on the DSM-5 diagnostic criteria; age range between 18 and 35 years; age of onset \< 2 years; severe or moderate depression based on scores on the Hamilton Depressive Rating Scale (HAM-D; scores between 14 and 24); severe or moderate anxiety based on scores on the Hamilton Anxiety Rating Scale (HAM-A; scores between 18 and 30); patients must have both severe/moderate depression and anxiety to be included; ability and willingness to provide informed consent and adhere to study procedures.
• Healthy controls group: age range between 18 and 35 years; ability and willingness to provide informed consent and adhere to study procedures.

You may not qualify if:

• Patients group: diagnosis of other Axis I and/or Axis II psychiatric conditions; substance and/or alcohol abuse and/or dependence; tumors or liver disorders; cognitive impairment.
• Healthy controls: history of Axis I psychiatric conditions in first-degree relatives; presence of preexisting neurological conditions; substance and/or alcohol abuse and/or dependence; cognitive impairment.

Sponsors & Collaborators

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: lead
• CNR Institute of Neuroscience, Parma: collaborator
• University of Trieste: collaborator
• IRCCS Fondazione Stella Maris: collaborator

Study Sites (1)

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico

Milan, MI, 20100, Italy

RECRUITING

Related Publications (5)

• Gorwood P. Generalized anxiety disorder and major depressive disorder comorbidity: an example of genetic pleiotropy? Eur Psychiatry. 2004 Feb;19(1):27-33. doi: 10.1016/j.eurpsy.2003.10.002.

  PMID: 14969778 BACKGROUND

• Zhou Y, Cao Z, Yang M, Xi X, Guo Y, Fang M, Cheng L, Du Y. Comorbid generalized anxiety disorder and its association with quality of life in patients with major depressive disorder. Sci Rep. 2017 Jan 18;7:40511. doi: 10.1038/srep40511.

  PMID: 28098176 BACKGROUND

• Jaso BA, Niciu MJ, Iadarola ND, Lally N, Richards EM, Park M, Ballard ED, Nugent AC, Machado-Vieira R, Zarate CA. Therapeutic Modulation of Glutamate Receptors in Major Depressive Disorder. Curr Neuropharmacol. 2017;15(1):57-70. doi: 10.2174/1570159x14666160321123221.

  PMID: 26997505 BACKGROUND

• Abdallah CG, Jiang L, De Feyter HM, Fasula M, Krystal JH, Rothman DL, Mason GF, Sanacora G. Glutamate metabolism in major depressive disorder. Am J Psychiatry. 2014 Dec 1;171(12):1320-7. doi: 10.1176/appi.ajp.2014.14010067. Epub 2014 Oct 31.

  PMID: 25073688 BACKGROUND

• Hastings RS, Parsey RV, Oquendo MA, Arango V, Mann JJ. Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression. Neuropsychopharmacology. 2004 May;29(5):952-9. doi: 10.1038/sj.npp.1300371.

  PMID: 14997169 BACKGROUND

MeSH Terms

Conditions

Depression; Anxiety Disorders

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior; Mental Disorders

Study Officials

• Sara Maria Pozzoli, PhD

  S. C. Psichiatria - Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Paolo Brambilla, Professor

CONTACT

02 55035982; paolo.brambilla@policlinico.mi.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 22, 2023
• First Posted: December 12, 2023
• Study Start: July 15, 2022
• Primary Completion: July 14, 2024
• Study Completion: July 14, 2025
• Last Updated: December 12, 2023

Record last verified: 2023-05

Locations

IT (1)