Inflammatory Control of Antidepressant Efficacy: a Pharmaco-epigenetic Approach

Major Depressive Disorder Clinical Trial

Official title:

Inflammatory Control of Antidepressant Efficacy: a Pharmaco-epigenetic Approach

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06306209
• Other study ID #: DeFLAME
• Status: Recruiting
• Start date: May 18, 2021
• Est. completion date: January 14, 2025

Study information

• Verified date: March 2024
• Source: IRCCS San Raffaele
• Contact: Sara Poletti, phd
• Phone: +390226433156
• Email: poletti.sara[@]hsr.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Major depressive disorder (MDD) is a chronic, recurring and potentially life-threatening illness that affects up to 10% of the population across the globe.It posits that the increase in serotonin levels induced by Selective Serotonin Reuptake Inhibitors (SSRIs) does not affect mood per se, but enhances brain plasticity and thus amplifies the influence of the environment on the individual. Thus, SSRI treatment has not a univocal effect but, in a favorable environment, it would lead to a reduction of symptoms while in a stressful environment might lead to a worse prognosis.Such innovative view opens new perspectives on how to improve SSRI efficacy by controlling the environment. However, often it is not possible to act on the quality of the living environment because of constraints due to patient's personal history and unchangeable life circumstances. In these cases, the pharmacological modulation of the factors underlying the link between living environment and SSRI efficacy represents a novel and desirable strategy to improve treatment outcome even in patients living in adverse conditions, which are very common in depressed patients. Inflammatory levels are markedly affected by the socioeconomic status and thus by the quality of the living environment. The hypothesis of the present project is that inflammation mediates the influence of the environment on SSRI outcome.Therefore, the control of inflammatory levels is a promising strategy to improve treatment efficacy and overcome the limited SSRI efficacy, especially when administered in patients living in adverse conditions. A further hypothesis is that the influence of the environment on inflammation, in turn affecting SSRI efficacy, occurs through epigenetic modifications. Therefore, the project aims at developing a pharmaco-epigenetic approach as effective treatment for MDD. In addition, through neuroimaging investigations, it will provide important information about functional and structural brain modifications associated to SSRI efficacy in patients.

Both males and females will be considered because MDD is twice as common in women than men, suggesting that different mechanisms may underlie the psychopathology in the two sexes.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: January 14, 2025
• Est. primary completion date: November 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

A depressive episode according to Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria in the course of MDD with:

HDRS score > 17 Age 18-65 years; In treatment with SSRIs Signed informed consent, able to understand, speak and write the national language

Exclusion Criteria:

• History of bipolar disorder, schizophrenia, schizoaffective disorder, psychosis not otherwise specified; anorexia or bulimia nervosa;

• Taking following medications: antipsychotics, anticonvulsants, mood stabilizers; stimulants

• Active infection requiring antibiotics therapy;

• Immunosuppressed patient

• Other chronic diseases

• Signs of active infection requiring treatment

• Use of anti-inflammatory medication on a regular basis for a chronic inflammatory/autoimmune Disorder.

• Forbidden treatment: corticosteroids, Non Steroidal Anti-inflammatory Drugs, immunosuppressant IV-Ig based treatment

• Ongoing fever, infection treated by antibiotics or uncontrolled diabetes type I or II;

• Existing cancer or history of cancer in the last 5 years (except skin epidermoid cancer or in-situ cervix cancer);

• Known HIV infection or clinically manifest Acquired Immune Deficiency Syndrome (AIDS),

• Parkinson's or Alzheimer's disease, or any other serious condition likely to interfere e with the conduct of the trial;

• Abuse of drugs or alcohol in the past 6 months

Related Conditions & MeSH terms

• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder
• Mood Disorders

Intervention

Other:
• Treatment as usual (TAU), i.e., pharmacotherapy plus clinical management
All participants enrolled in the study will receive Treatment as usual (TAU), i.e., pharmacotherapy plus clinical management. Clinicians will be free to choose antidepressant medication, doses and drug combinations, including augmentations strategies and non-pharmacological treatments, which will follow standard clinical treatment guidelines for MDD.

Locations

Country	Name	City	State
Italy	IRCCS Ospedale San Raffaele	Milan	Mi

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS San Raffaele

Country where clinical trial is conducted

Italy, 

References & Publications (22)

Alboni S, van Dijk RM, Poggini S, Milior G, Perrotta M, Drenth T, Brunello N, Wolfer DP, Limatola C, Amrein I, Cirulli F, Maggi L, Branchi I. Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment. Mol Psychiatry. 2017 Apr;22(4):552-561. doi: 10.1038/mp.2015.142. Epub 2015 Sep 15. Erratum In: Mol Psychiatry. 2017 Apr;22(4):635. — View Citation

Alley DE, Seeman TE, Ki Kim J, Karlamangla A, Hu P, Crimmins EM. Socioeconomic status and C-reactive protein levels in the US population: NHANES IV. Brain Behav Immun. 2006 Sep;20(5):498-504. doi: 10.1016/j.bbi.2005.10.003. Epub 2005 Dec 2. — View Citation

Belsky J, Jonassaint C, Pluess M, Stanton M, Brummett B, Williams R. Vulnerability genes or plasticity genes? Mol Psychiatry. 2009 Aug;14(8):746-54. doi: 10.1038/mp.2009.44. Epub 2009 May 19. — View Citation

Benedetti F, Poletti S, Hoogenboezem TA, Locatelli C, de Wit H, Wijkhuijs AJM, Colombo C, Drexhage HA. Higher Baseline Proinflammatory Cytokines Mark Poor Antidepressant Response in Bipolar Disorder. J Clin Psychiatry. 2017 Sep/Oct;78(8):e986-e993. doi: 10.4088/JCP.16m11310. — View Citation

Branchi I, Santarelli S, Capoccia S, Poggini S, D'Andrea I, Cirulli F, Alleva E. Antidepressant treatment outcome depends on the quality of the living environment: a pre-clinical investigation in mice. PLoS One. 2013 Apr 30;8(4):e62226. doi: 10.1371/journal.pone.0062226. Print 2013. — View Citation

Branchi I. The double edged sword of neural plasticity: increasing serotonin levels leads to both greater vulnerability to depression and improved capacity to recover. Psychoneuroendocrinology. 2011 Apr;36(3):339-51. doi: 10.1016/j.psyneuen.2010.08.011. Epub 2010 Sep 26. — View Citation

Carvalho LA, Torre JP, Papadopoulos AS, Poon L, Juruena MF, Markopoulou K, Cleare AJ, Pariante CM. Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J Affect Disord. 2013 May 15;148(1):136-40. doi: 10.1016/j.jad.2012.10.036. Epub 2012 Nov 27. — View Citation

Cattaneo A, Ferrari C, Uher R, Bocchio-Chiavetto L, Riva MA; MRC ImmunoPsychiatry Consortium; Pariante CM. Absolute Measurements of Macrophage Migration Inhibitory Factor and Interleukin-1-beta mRNA Levels Accurately Predict Treatment Response in Depressed Patients. Int J Neuropsychopharmacol. 2016 Sep 30;19(10):pyw045. doi: 10.1093/ijnp/pyw045. Print 2016 Oct. — View Citation

Chiarotti F, Viglione A, Giuliani A, Branchi I. Citalopram amplifies the influence of living conditions on mood in depressed patients enrolled in the STAR*D study. Transl Psychiatry. 2017 Mar 21;7(3):e1066. doi: 10.1038/tp.2017.35. — View Citation

Cohen A, Houck PR, Szanto K, Dew MA, Gilman SE, Reynolds CF 3rd. Social inequalities in response to antidepressant treatment in older adults. Arch Gen Psychiatry. 2006 Jan;63(1):50-6. doi: 10.1001/archpsyc.63.1.50. — View Citation

Dinan TG. Inflammatory markers in depression. Curr Opin Psychiatry. 2009 Jan;22(1):32-6. doi: 10.1097/YCO.0b013e328315a561. — View Citation

Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry. 2009 Sep 1;66(5):407-14. doi: 10.1016/j.biopsych.2009.03.015. Epub 2009 May 7. — View Citation

Hepgul N, Cattaneo A, Agarwal K, Baraldi S, Borsini A, Bufalino C, Forton DM, Mondelli V, Nikkheslat N, Lopizzo N, Riva MA, Russell A, Hotopf M, Pariante CM. Transcriptomics in Interferon-alpha-Treated Patients Identifies Inflammation-, Neuroplasticity- and Oxidative Stress-Related Signatures as Predictors and Correlates of Depression. Neuropsychopharmacology. 2016 Sep;41(10):2502-11. doi: 10.1038/npp.2016.50. Epub 2016 Apr 12. — View Citation

Iosifescu DV, Clementi-Craven N, Fraguas R, Papakostas GI, Petersen T, Alpert JE, Nierenberg AA, Fava M. Cardiovascular risk factors may moderate pharmacological treatment effects in major depressive disorder. Psychosom Med. 2005 Sep-Oct;67(5):703-6. doi: 10.1097/01.psy.0000170338.75346.d0. — View Citation

Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, De Pasquale R, O'Leary OF, Castren E, Maffei L. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science. 2008 Apr 18;320(5874):385-8. doi: 10.1126/science.1150516. — View Citation

Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009 May 1;65(9):732-41. doi: 10.1016/j.biopsych.2008.11.029. Epub 2009 Jan 15. — View Citation

Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016 Jan;16(1):22-34. doi: 10.1038/nri.2015.5. — View Citation

Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF. Major depressive disorder. Nat Rev Dis Primers. 2016 Sep 15;2:16065. doi: 10.1038/nrdp.2016.65. — View Citation

Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013 Jan;70(1):31-41. doi: 10.1001/2013.jamapsychiatry.4. — View Citation

Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006 Jan;163(1):28-40. doi: 10.1176/appi.ajp.163.1.28. — View Citation

Vogelzangs N, Beekman AT, van Reedt Dortland AK, Schoevers RA, Giltay EJ, de Jonge P, Penninx BW. Inflammatory and metabolic dysregulation and the 2-year course of depressive disorders in antidepressant users. Neuropsychopharmacology. 2014 Jun;39(7):1624-34. doi: 10.1038/npp.2014.9. Epub 2014 Jan 20. — View Citation

WHO, 2008 The global burden of disease: 2004 update

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The potential role of inflammation as the causal link between the quality of the environment and SSRI efficacy	we will measure the levels of peripheral inflammatory markers and implement mediation/moderation model to investigate if inflammatory markers mediate/moderate the association between the environment (number of stressful events) and SSRIs efficacy (response to treatment: 50% reduction at the hamilton depression rating scale (HDRS) - scores min 0 max 52, higher score higher severity).	Blood samples will be collected at baseline time and after 3 months in correspondence with routine blood sampling performed at the patients arrival in the hospital.
Primary	interaction between early stress and recent stress on the response to treatment and the role of inflammation	we will investigate whether patients exposed to early stress (Risk Families Questionnaire (RFQ) score min 13, max 65, higher scores higher exposure to early life events;Childhood Trauma Questionnaire (CTQ) score min 28, max 140, higher score higher childhood trauma) have higher levels of inflammatory markers and are more vulnerable to recent stress (number of events) and if this interaction affects the response to treatment (50% reduction at HDRS)	at baseline, at 3 months follow up
Primary	identification of neurobiological predictors of response to treatment	MRI scans will be performed at baseline and 3 month followup (Functional MRI). Changes in gray matter volumes which predict response to treatment (50% reduction at HDRS)will be identified	at baseline, at 3 months follow up
Primary	identification of neurobiological predictors of response to treatment	MRI scans will be performed at baseline and 3 month followup (Diffusion Tensor Imaging (DTI);) Changes in white matter microstructure (fractional anisotropy) which predict response to treatment (50% reduction at HDRS)will be identified	at baseline, at 3 months follow up
Primary	identification of neurobiological predictors of response to treatment	Changes in peripheral inflammatory markers and transcriptomic between baseline and follow-up able to predict response to treatment (50% reduction at HDRS) will be identified	at baseline, at 3 months follow up, at 6 months follow up
Secondary	epigenetic changes in cytokine regulating genes which could mediate the effect of stress on response to treatment.	mediation/moderation models will be implemented to identify epigenetic changes (RNA sequencing) that mediate/moderate the association between recent stress (number of events) and response to treatment (50% reduction at HDRS)	Blood samples will be collected at baseline time and after 3 months in correspondence with routine blood sampling performed at the patients arrival in the hospital.