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Tianeptine for Treatment Resistant Depression

Primary Purpose

Treatment Resistant Depression

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Tianeptine Sodium
Sponsored by
New York State Psychiatric Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Treatment Resistant Depression

Eligibility Criteria

21 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age 21-50 years, male or female
  2. Current diagnosis of Unipolar Major Depressive Disorder (MDD) without psychotic features
  3. 24-item Hamilton Rating Scale for Depression (HRSD) ≥ 16
  4. At least two previous antidepressant treatment failures (adequate trial within current episode) with an SSRI, SNRI, bupropion, tricyclic antidepressant, mirtazapine, nefazodone, monoamine oxidase inhibitor, or transcranial magnetic stimulation (TMS)
  5. Capable of providing informed consent and complying with study procedures
  6. Currently using or willing to use contraception, if woman of childbearing potential (such as condoms, IUD, or oral contraceptive), for duration of the study

Exclusion Criteria:

  1. Any history of opioid-use disorder
  2. Any history of moderate- non-opioid (except for Nicotine) substance-use disorder
  3. Any severity of alcohol use disorder (including mild)
  4. Past or current psychosis, psychotic disorder (including psychotic MDD), mania, or bipolar disorder
  5. Hamilton Rating Scale for Depression (HRSD) suicide item > 2 or Clinical Global Impressions (CGI)-Severity score of 7 at baseline
  6. Previous or current treatment with tianeptine
  7. Current treatment or currently taking an opioid
  8. Failed depression treatment with electroconvulsive therapy, intravenous ketamine or esketamine
  9. Acute, severe, or unstable medical illness
  10. Weight > 300 lbs or girth size incompatible with scanner bore
  11. Any physical or intellectual disability adversely affecting ability to complete assessments; MMSE <26
  12. Having contraindication to MRI scanning (such as metal in body) or inability to tolerate the scanning procedures (e.g., severe obesity, claustrophobia)
  13. Current pregnancy or currently breast feeding
  14. Abnormal baseline liver function tests
  15. Currently being treated with an antidepressant medication, an antipsychotic or mood stabilizer and not willing to end current treatment
  16. Positive urine toxicity at screening (except for cannabinoid)

Sites / Locations

  • Stanford Depression Research Clinic at Stanford University School of MedicineRecruiting
  • Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount SinaiRecruiting
  • New York State Psychiatric Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Open Treatment

Arm Description

All subjects will be treated for 8 weeks of treatment with Tianeptine (Tianeurax 12.5 mg) 3 times a day (9am, 1pm, 5pm).

Outcomes

Primary Outcome Measures

Hamilton Rating Scale for Depression (HRSD)
Our target is depressive symptomatology as measured by the Hamilton Rating Scale for Depression (HRSD). The HRSD is a 24-item questionnaire used as an indication of depression and a guide to evaluate recovery. Total scores range from 0-74, not including atypical symptoms sub-scale. A score of 16 or above is typically considered to indicate the presence of depressive symptoms. Higher scores indicate greater severity.

Secondary Outcome Measures

Full Information

First Posted
January 29, 2020
Last Updated
June 15, 2023
Sponsor
New York State Psychiatric Institute
Collaborators
Icahn School of Medicine at Mount Sinai, Stanford University
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1. Study Identification

Unique Protocol Identification Number
NCT04249596
Brief Title
Tianeptine for Treatment Resistant Depression
Official Title
Tianeptine for Treatment Resistant Depression
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 14, 2020 (Actual)
Primary Completion Date
June 1, 2025 (Anticipated)
Study Completion Date
June 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
New York State Psychiatric Institute
Collaborators
Icahn School of Medicine at Mount Sinai, Stanford University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
The studies will be conducted in parallel at two sites: the the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai (MSSM), and Stanford Depression Research Clinic at Stanford University School of Medicine (SUSM). In addition, MRI studies for the MSSM patients will be carried out at the New York State Psychaitric Institute (NYSPI). The following procedures will be approved by the local Institutional Review Boards (IRBs) at each site, where the site PIs (Alla Landa, PhD, NYSPI, James Murrough, MD at MSSM, and Alan Schatzberg, MD at SUSM) will be responsible for overseeing conduct of the study at their respective site. Dr. Jonathan Javitch is the scientific leader of this program and holds the IND for tianeptine use in this study. Investigators will recruit 75 participants with current unipolar MDD, non-delusional, between 21-60, who have failed at least 2 two adequate treatment trials with a standard antidepressant. Patients will receive an 8-week treatment trial of tianeptine. MSSM patients will also undergo structural and task-based magnetic resonance imaging (MRI) that will be performed under Dr. Landa's direction at NYSPI in order to maintain the internal validity of the data set. MSSM subjects will be transported to NYSPI to complete neuroimaging procedures as described below. Participants will be screened for MRI clearance during their screening visit and again at NYSPI on the day of the scan. Subjects will be asked MRI screening questions to ensure that are scanning eligible. Participants will also have additional tubes of blood drawn for human whole-genomic testing. This microarray will be used to identify regions of the human genome that contribute to disease susceptibility and phenotypes. The Illumina human whole-genome array will be used to provide a comprehensive view of the genome, detects single nucleotide polymorphisms and other variations across the genome.
Detailed Description
Major depressive disorder (MDD) is a leading cause of disability in adults worldwide (~16M patients in United States alone). Unfortunately, only 35-40% of patients achieve full remission following first-line treatment and treatment-resistant depression (TRD), failure to respond to 2 or more treatments, is a critical clinical problem. As with MDD, there is mechanistic heterogeneity in TRD and consequently, there is a need to develop treatments targeted to biologically distinct subgroups of patients. Significant evidence suggests dysfunction of endogenous opioid signaling pathways as a key biological deficit in some MDD patients. Investigators hypothesize that a subgroup of MDD patients with deficient opioid receptor signaling who have failed previous trials of antidepressants will better respond to pharmacological interventions specifically targeting this biological mechanism. In this application, Investigators propose to target the mu-opioid receptor (MOR) in TRD patients by using the antidepressant tianeptine. Although not available in the United States, Tianeptine is an atypical antidepressant that has been used clinically in Europe, Asia, and South America since the late 1980s in millions of patients. Until recently tianeptine's molecular mechanism of action had remained unknown. Tianeptine is a different type of antidepressant than those currently approved in the United States in that it has a different mechanism of action than other antidepressants. Tianeptine is an opioid antagonist; it binds at the mu-opioid receptor. Currently approved antidepressants act on other systems of the brain that primarily affect serotonin, norepinephrine, and dopamine. Work in our laboratories has shown that tianeptine acts as a selective agonist of MOR, signaling in a manner analogous to enkephalins and endorphins, the endogenous opioid peptides. The investigator applied for and received an IND to import and use tianeptine for this study. The studies will be conducted in parallel at two sites: the the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai (MSSM), and Stanford Depression Research Clinic at Stanford University School of Medicine (SUSM). In addition, MRI studies for the MSSM patients will be carried out at the New York State Psychaitric Institute (NYSPI). The following procedures will be approved by the local Institutional Review Boards (IRBs) at each site, where the site PIs (Alla Landa, PhD, NYSPI, James Murrough, MD at MSSM, and Alan Schatzberg, MD at SUSM) will be responsible for overseeing conduct of the study at their respective site. Dr. Jonathan Javitch is the scientific leader of this program and holds the IND for tianeptine use in this study. Investigators will recruit 75 participants with current unipolar MDD, non-delusional, between 21-60, who have failed at least 2 two adequate treatment trials with a standard antidepressant. MSSM patients will also undergo structural and task-based magnetic resonance imaging (MRI) that will be performed under Dr. Steven Landa's direction at NYSPI in order to maintain the internal validity of the data set. MSSM subjects will be transported to NYSPI to complete neuroimaging procedures as described below. Participants will be screened for MRI clearance during their screening visit and again at NYSPI on the day of the scan. Subjects will be asked MRI screening questions to ensure that are scanning eligible. Participants will also have additional tubes of blood drawn for human whole-genomic testing. This microarray will be used to identify regions of the human genome that contribute to disease susceptibility and phenotypes. The Illumina human whole-genome array will be used to provide a comprehensive view of the genome, detects single nucleotide polymorphisms and other variations across the genome. The major goals of this project are (1) to determine if tianeptine is an effective antidepressant in patients who have failed two previous trials, (2) to define the relationship between opioid signaling deficits and response to tianeptine treatment, and (3) to develop a comprehensive assessment battery capable of identifying endogenous opioid signaling deficits to explore biological heterogeneity in the TRD population.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Treatment Resistant Depression

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
75 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Open Treatment
Arm Type
Experimental
Arm Description
All subjects will be treated for 8 weeks of treatment with Tianeptine (Tianeurax 12.5 mg) 3 times a day (9am, 1pm, 5pm).
Intervention Type
Drug
Intervention Name(s)
Tianeptine Sodium
Other Intervention Name(s)
Tianeurex 12.5 mg
Intervention Description
At baseline, and following 8 weeks of treatment with tianeptine(12.5 mg, 3x daily), participants will be assessed in a number of procedures to evaluate their emotional and physical pain state and pain stimulus response and the relationship of such states/responses to endogenous opioid signaling. To further assess emotional pain, participants will also undergo fMRI while performing a validated social rejection and social acceptance paradigm known to induce endogenous opioid release in control subjects and blunted release in MDD. Examining both rejection and acceptance is important because the MOR system regulates both social distress and social reward in animals and humans, and tianeptine may also act on abnormal MOR-mediated responses to social acceptance in MDD. Likewise, a second fMRI scan will be used to explore physical pain response using an established thermal pain sensitivity task. The protocol at Stanford University will not include pain testing or imaging studies.
Primary Outcome Measure Information:
Title
Hamilton Rating Scale for Depression (HRSD)
Description
Our target is depressive symptomatology as measured by the Hamilton Rating Scale for Depression (HRSD). The HRSD is a 24-item questionnaire used as an indication of depression and a guide to evaluate recovery. Total scores range from 0-74, not including atypical symptoms sub-scale. A score of 16 or above is typically considered to indicate the presence of depressive symptoms. Higher scores indicate greater severity.
Time Frame
Baseline

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 21 - 60 years, male or female Current diagnosis of Major Depressive Disorder (MDD) without psychotic features 24-item Hamilton Rating Scale for Depression (HRSD) ≥ 16 At least two previous antidepressant treatment failures (adequate trials within current episode) with a SSRI, SNRI, bupropion, tricyclic antidepressant, mirtazapine, nefazodone, or monoamine oxidase inhibitor, or transcranial magnetic stimulation (TMS), or IV ketamine or nasal ketamine. Capable of providing informed consent and complying with study procedures Currently using or willing to use contraception, if woman of childbearing potential (such as condoms, IUD, or oral contraceptive), for duration of the study. Exclusion Criteria: Any history of opioid-use disorder Any history of moderate- non-opioid (except for Nicotine) substance-use disorder. Any severity of alcohol use disorder (including mild) Past or current psychosis, psychotic disorder (including psychotic MDD), mania, or bipolar disorder Hamilton Rating Scale for Depression (HRSD) suicide item > 2 or Clinical Global Impressions (CGI)-Severity score of 7 at baseline Previous or current treatment with Tianeptine Current treatment or currently taking an opioid. Failed depression treatment with electroconvulsive therapy. Acute, severe, or unstable medical illness Weight > 300 lbs, or girth size incompatible with scanner bore. Any physical or intellectual disability adversely affecting ability to complete assessments. MMSE <26 for MSSM site - Having contraindication to MRI scanning (such as metal in body) or inability to tolerate the scanning procedures (e.g., severe obesity, claustrophobia) Current pregnancy or currently breast feeding. Abnormal baseline liver function tests Currently being treated with an antidepressant medication, an antipsychotic or mood stabilizer. a) If a participant is taking a protocol dis-allowed medication at the time of screening and despite medication treatment still meets the inclusion criteria of an HRSD>16, the participant may discontinue the medication under the supervision of their treating physician or the study clinician. Positive urine toxicity at screening (except for cannabinoid)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Steven Roose, MD
Phone
646-774-8661
Email
spr2@cumc.columbia.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Alla Landa, PhD
Phone
646-774-6717
Email
al2898@cumc.columbia.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alla Landa, PhD
Organizational Affiliation
New York State Psychiatric Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford Depression Research Clinic at Stanford University School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jessica Hawkins
Phone
650-723-8330
Email
jhawk@stanford.edu
First Name & Middle Initial & Last Name & Degree
Alan Schatzberg, MD
First Name & Middle Initial & Last Name & Degree
Charles DeBattista, MD
Facility Name
Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Amelia Karim
Phone
212-585-6133
Email
amelia.karim@mssm.edu
First Name & Middle Initial & Last Name & Degree
James Murrough, M.D.
Facility Name
New York State Psychiatric Institute
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Active, not recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

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Tianeptine for Treatment Resistant Depression

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