Tianeptine for Treatment Resistant Depression

Phase 4

Recruiting

• Conditions: Treatment Resistant Depression
• Interventions: Drug: Tianeptine Sodium

• Registration Number: NCT04249596
• Lead Sponsor: New York State Psychiatric Institute

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. Alla 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.

Study Timeline

• Study First Submitted: 2020-01-29
• Study First Submitted QC: 2020-01-29
• Study First Posted: 2020-01-31
• Study Start: 2020-10-14
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-02
• Last Update Posted: 2024-07-03
• Primary Completion: 2025-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 75

Inclusion Criteria

1. Age 21 - 60 years, male or female
2. Current diagnosis of 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 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.
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.

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. 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)

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.

    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.

16. Positive urine toxicity at screening (except for cannabinoid)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Hamilton Rating Scale for Depression (HRSD)	Baseline	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.

Trial Locations

Locations (3)

Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai; 🇺🇸 New York, New York, United States

Stanford Depression Research Clinic at Stanford University School of Medicine; 🇺🇸 Stanford, California, United States

New York State Psychiatric Institute; 🇺🇸 New York, New York, United States