Inflammatory Control of Antidepressant Efficacy: a Pharmaco-epigenetic Approach

NCT06306209 | Recruiting

• 1 other identifier: DeFLAME
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Mood Disorders; Major Depressive Disorder

Outcome Measures

Primary Outcomes (5)

• 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.

• 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

• 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

• 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

• 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 Outcomes (1)

• epigenetic changes in cytokine regulating genes which could mediate the effect of stress on response to treatment.

  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.

Study Arms (1)

MDD

80 patients with a depressive episode in course of major depression (MDD) and treated with SSRI's will be studied. The study does not include the evaluation of pharmacological treatments. The treatments will be administered in the judgment of the attending physician, independently of the experimental protocol.

Other: Treatment as usual (TAU), i.e., pharmacotherapy plus clinical management

Interventions

Treatment as usual (TAU), i.e., pharmacotherapy plus clinical management OTHER

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.

MDD

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients are always informed on currently ongoing and upcoming (clinical) duties during their regular outpatient clinic visits and at the first interview during hospitalization

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• IRCCS San Raffaele: lead

Study Sites (1)

IRCCS Ospedale San Raffaele

Milan, Mi, 20132, Italy

RECRUITING

Related Publications (22)

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• WHO, 2008 The global burden of disease: 2004 update

  BACKGROUND

MeSH Terms

Conditions

Mood Disorders; Depressive Disorder, Major

Interventions

Therapeutics; Drug Therapy

Condition Hierarchy (Ancestors)

Mental Disorders; Depressive Disorder

Study Officials

• sara Poletti, PhD

  IRCCS Ospedale San Raffaele

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sara Poletti, phd

CONTACT

+390226433156; poletti.sara@hsr.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 27, 2024
• First Posted: March 12, 2024
• Study Start: May 18, 2021
• Primary Completion: November 30, 2024
• Study Completion: January 14, 2025
• Last Updated: March 12, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)