The Role of Negr1 In Modulating Neuroplasticity in Major Depression (RONIN)

NCT06131268 | Unknown Phase 4

• 1 other identifier: RONIN
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Patients belonging to Group 1 (Major Depression) and 2 (Bipolar Disorder) will be tested with psychometric and functional scales at baseline (T0) and after 4 weeks of pharmacological therapy (T1), to evaluate clinical and functional response to treatment. MDD patients will be screened for the lifetime and recent occurrence of clinically meaningful suicidal ideation and behavior prior to recruitment (-T1). Moreover, in the MDD group, the emergence of clinically meaningful suicidal ideation and behavior will be evaluated at the baseline (T0) and after 4 weeks (T1) by means of the C-SSRS, accordingly to the routine clinical practice. Furtherly, to accomplish the pursues of this research, the two groups will undergo neuroimaging evaluation and a blood collection at the two timepoints for measuring the expression of ncRNA before and after treatment. Meanwhile, a lumbar puncture (LP) for CSF collection will be carried out at the baseline, measuring central levels of Negr-1 and other biomarkers of neurotropism potentially related to the aforementioned role of Negr1 in MDD. Group 3 will be comprehensive of 10 subjects without current or previous diagnosis of psychiatric disorders (healthy controls), who will be evaluated at baseline with psychometric and functional scales, neuroimaging and blood samples collection for ncRNA. Data obtained by the multimodal assessment of HCs at the baseline will be employed as normalization features in the statistical analysis of patients' data.

Conditions

Major Depressive Disorder; Bipolar Affective Disorder, Currently Depressed, Moderate

Keywords

major depressive disorder; NEGR1 protein; antidepressants; venlafaxina; NEGR1 mRna; brain connectivity

Outcome Measures

Primary Outcomes (1)

• evaluate if venlafaxine induced a change in Negr1 gene expression in the whole blood of venlafaxine-treated MDD patients compared to antidepressant-free BD patients experiencing a depressive episode.

  To observe a significant (p\<0.05 at t test for continuous variable) differential concentration of Negr1 transcript (mRNA) and protein withing the T0 and T1 (4 weeks) in MDD patients treated with venlafaxine, respect to the antidepressant-free BD patient. The differential expression of Negr1 will be calculated for both patients' groups (MDD and BD) as the absolute variation between the blood Negr1 mRNA and plasmatic protein concentration measured at T0 and T1.

  4 weeks

Secondary Outcomes (5)

• To test the hypothesis that venlafaxine improves resting state brain connectivity in MDD patients through the modulation of Negr1 pathway, compared to venlafaxine-free BD patients

  4 weeks

• To evaluate the variation of molecules able to modulate Negr1 gene expression or participating in Negr1 pathway between BD and MDD groups and within each single group over the follow-up period

  4 weeks

• To identify blood-based biomarkers of MDD

  4 weeks

• To identify neuroimaging biomarkers of MDD

  4 weeks

• To cross-sectionally assess the correspondence between central (CSF) and peripheral (whole blood) expression levels of Negr1 and related gene within MDD and BD groups at the baseline.

  4 weeks

Study Arms (3)

Patients with Major Depression (Group 1)

EXPERIMENTAL

They will be evaluated at baseline (T0) and at 4 weeks from the setting of drug treatment with venlafaxine (T1)

Drug: Venlafaxine

Bipolar disorder patients (Group 2)

NO INTERVENTION

Venlafaxine will not be administered. They will be valuated both at T0 and after 4 weeks (T1).

Healthy controls (Group 3)

NO INTERVENTION

Venlafaxine will not be administered. They will be evaluated only at baseline (T0).

Interventions

Venlafaxine DRUG

we will recruit a cohort of 10 MDD patients currently receiving evidence-based treatments for depression (including treatment with an antidepressant drug such as SSRIs/SNRIs) who will be switched to the antidepressant venlafaxine and followed along for 4 weeks (Group 1). The switch from the ongoing treatment to venlafaxine will must be required by therapeutical needs (null or partial response and/or poor tolerability or compliance to ongoing therapy) according to the indications of the principle clinical guidelines for the treatment of MDD and it is independent of the decision of including the patient in the study.

Patients with Major Depression (Group 1)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• GRUPPO 1: Recently diagnosed MDD, ongoing depressive episode, as determined by SCID-CV;
• Clinical indication to switch from current antidepressant therapy to venlafaxine due to lack of efficacy and/or tolerance and/or compliance.
• GRUPPO 2: Recent diagnosis of BD with a current depressive episode, as determined by SCID-CV;
• \- absence of antidepressants in the patient's drug regimen.
• GRUPPO 3: No diagnosis of psychiatric disorders made as a result of SCID-CV.

You may not qualify if:

• GRUPPO 1: - treatment with venlafaxine ongoing or within 6 months before the recruitment
• concomitant treatment with an irreversible MonoAmine Oxidase Inhibitor (I-MAO) or interruption of the IMAO treatment before 14 days from the recruitment;
• pregnant and breastfeeding woman;
• Lifetime comorbidity for psychotic disorders, as determined by the SCID-CV;
• Lifetime or recent history of suicide attempts or suicide-related behaviors and ideation (lifetime and/or recent C-SSRS Ideation or Behavior sub-score \>0);
• Current, clinically meaningful, substance use disorders;
• Current comorbidity with neurological conditions or severe head trauma; -Neuropsychological diagnosis of intellectual disability;
• Presence of contraindications to lumbar puncture or MRI
• known hypersensitivity to the active substance venlafaxine or to any of the excipients
• Women of Childbearing Potential without a negative pregnancy test and not undertaking a high effective anticonception treatment at the recruitment
• GRUPPO 2:
• Lifetime comorbidity for psychotic disorders, as determined by the SCID-CV;
• Current, clinically meaningful, substance use disorders;
• Current comorbidity with neurological conditions or severe head trauma;
• Neuropsychological diagnosis of intellectual disability;

Sponsors & Collaborators

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: lead

Study Sites (1)

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico

Milan, MI, 20100, Italy

RECRUITING

Related Publications (15)

• Barreto RA, Walker FR, Dunkley PR, Day TA, Smith DW. Fluoxetine prevents development of an early stress-related molecular signature in the rat infralimbic medial prefrontal cortex. Implications for depression? BMC Neurosci. 2012 Oct 18;13:125. doi: 10.1186/1471-2202-13-125.

  PMID: 23075086 BACKGROUND

• Brakowski J, Spinelli S, Dorig N, Bosch OG, Manoliu A, Holtforth MG, Seifritz E. Resting state brain network function in major depression - Depression symptomatology, antidepressant treatment effects, future research. J Psychiatr Res. 2017 Sep;92:147-159. doi: 10.1016/j.jpsychires.2017.04.007. Epub 2017 Apr 24.

  PMID: 28458140 BACKGROUND

• Braun U, Schaefer A, Betzel RF, Tost H, Meyer-Lindenberg A, Bassett DS. From Maps to Multi-dimensional Network Mechanisms of Mental Disorders. Neuron. 2018 Jan 3;97(1):14-31. doi: 10.1016/j.neuron.2017.11.007.

  PMID: 29301099 BACKGROUND

• Bromet EJ, Nock MK, Saha S, Lim CCW, Aguilar-Gaxiola S, Al-Hamzawi A, Alonso J, Borges G, Bruffaerts R, Degenhardt L, de Girolamo G, de Jonge P, Florescu S, Gureje O, Haro JM, He Y, Hu C, Karam EG, Kovess-Masfety V, Lee S, Lepine JP, Mneimneh Z, Navarro-Mateu F, Ojagbemi A, Posada-Villa J, Sampson NA, Scott KM, Stagnaro JC, Viana MC, Xavier M, Kessler RC, McGrath JJ; World Health Organization World Mental Health Survey Collaborators. Association Between Psychotic Experiences and Subsequent Suicidal Thoughts and Behaviors: A Cross-National Analysis From the World Health Organization World Mental Health Surveys. JAMA Psychiatry. 2017 Nov 1;74(11):1136-1144. doi: 10.1001/jamapsychiatry.2017.2647.

  PMID: 28854302 BACKGROUND

• Brown EC, Clark DL, Hassel S, MacQueen G, Ramasubbu R. Thalamocortical connectivity in major depressive disorder. J Affect Disord. 2017 Aug 1;217:125-131. doi: 10.1016/j.jad.2017.04.004. Epub 2017 Apr 5.

  PMID: 28407555 BACKGROUND

• Brunello N, Mendlewicz J, Kasper S, Leonard B, Montgomery S, Nelson J, Paykel E, Versiani M, Racagni G. The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. Eur Neuropsychopharmacol. 2002 Oct;12(5):461-75. doi: 10.1016/s0924-977x(02)00057-3.

  PMID: 12208564 BACKGROUND

• Burns DD, Spangler DL. Does psychotherapy homework lead to improvements in depression in cognitive-behavioral therapy or does improvement lead to increased homework compliance? J Consult Clin Psychol. 2000 Feb;68(1):46-56. doi: 10.1037//0022-006x.68.1.46.

  PMID: 10710839 BACKGROUND

• Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999 May;156(5):675-82. doi: 10.1176/ajp.156.5.675.

  PMID: 10327898 BACKGROUND

• Cederquist GY, Asciolla JJ, Tchieu J, Walsh RM, Cornacchia D, Resh MD, Studer L. Specification of positional identity in forebrain organoids. Nat Biotechnol. 2019 Apr;37(4):436-444. doi: 10.1038/s41587-019-0085-3. Epub 2019 Apr 1.

  PMID: 30936566 BACKGROUND

• Collins AL, Sullivan PF. Genome-wide association studies in psychiatry: what have we learned? Br J Psychiatry. 2013 Jan;202(1):1-4. doi: 10.1192/bjp.bp.112.117002.

  PMID: 23284144 BACKGROUND

• Cross-Disorder Group of the Psychiatric Genomics Consortium; Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayes M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisen L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kahler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landen M, Langstrom N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Muhleisen TW, Muir WJ, Muller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nothen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnstrom K, Reif A, Ribases M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zollner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR; International Inflammatory Bowel Disease Genetics Consortium (IIBDGC). Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013 Sep;45(9):984-94. doi: 10.1038/ng.2711. Epub 2013 Aug 11.

  PMID: 23933821 BACKGROUND

• DeRubeis RJ, Hollon SD, Amsterdam JD, Shelton RC, Young PR, Salomon RM, O'Reardon JP, Lovett ML, Gladis MM, Brown LL, Gallop R. Cognitive therapy vs medications in the treatment of moderate to severe depression. Arch Gen Psychiatry. 2005 Apr;62(4):409-16. doi: 10.1001/archpsyc.62.4.409.

  PMID: 15809408 BACKGROUND

• Dichter GS, Gibbs D, Smoski MJ. A systematic review of relations between resting-state functional-MRI and treatment response in major depressive disorder. J Affect Disord. 2015 Feb 1;172:8-17. doi: 10.1016/j.jad.2014.09.028. Epub 2014 Sep 26.

  PMID: 25451389 BACKGROUND

• Disner SG, Beevers CG, Haigh EA, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011 Jul 6;12(8):467-77. doi: 10.1038/nrn3027.

  PMID: 21731066 BACKGROUND

• Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997 Apr 24;386(6627):824-7. doi: 10.1038/386824a0.

  PMID: 9126739 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major; Bipolar Disorder; Lymphoma, Follicular

Interventions

Venlafaxine Hydrochloride

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Bipolar and Related Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cyclohexanols; Hexanols; Fatty Alcohols; Alcohols; Organic Chemicals; Phenethylamines; Ethylamines; Amines; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Lipids

Study Officials

• Giandomenico Schiena, Doctor

  Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Giandomenico Schiena, Doctor

CONTACT

02 5503 5982; giandomenico.schiena@policlinico.mi.it

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 13, 2023
• First Posted: November 14, 2023
• Study Start: March 1, 2022
• Primary Completion: March 1, 2024
• Study Completion: April 1, 2024
• Last Updated: November 14, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)