Inflammatory Control of Antidepressant Efficacy: a Pharmaco-epigenetic Approach

March 5, 2024 updated by: Sara Poletti, IRCCS San Raffaele

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Estimated)

80

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
    • Mi
      • Milan, Mi, Italy, 20132
        • Recruiting
        • Irccs Ospedale San Raffaele
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

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

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
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
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The potential role of inflammation as the causal link between the quality of the environment and SSRI efficacy
Time Frame: 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.
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
Time Frame: at baseline, at 3 months follow up
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
Time Frame: at baseline, at 3 months follow up
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
Time Frame: at baseline, at 3 months follow up
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
Time Frame: at baseline, at 3 months follow up, at 6 months follow up
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
epigenetic changes in cytokine regulating genes which could mediate the effect of stress on response to treatment.
Time Frame: 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.
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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS San Raffaele

Investigators

  • Principal Investigator: Sara Poletti, PhD, Irccs Ospedale San Raffaele

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 18, 2021

Primary Completion (Estimated)

November 30, 2024

Study Completion (Estimated)

January 14, 2025

Study Registration Dates

First Submitted

February 27, 2024

First Submitted That Met QC Criteria

March 5, 2024

First Posted (Actual)

March 12, 2024

Study Record Updates

Last Update Posted (Actual)

March 12, 2024

Last Update Submitted That Met QC Criteria

March 5, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DeFLAME

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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