Treatment Resistant DepressionPhase 4NCT04249596
Tianeptine for Treatment Resistant Depression
A Phase 4 study testing Tianeptine Sodium in people with Treatment Resistant Depression, run by Jonathan A. Javitch, MD, PhD at 3 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 21 to 60 years
- Conditions the study is for
- Treatment Resistant Depression
- What is being tested?
- Tianeptine Sodium
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 3 sitesUnited States
- Study dates
- 14 Oct 2020to 27 Aug 2024
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 17Show fewer
- 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.
- 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)
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai
New York, New York, 10029
New York State Psychiatric Institute
New York, New York, 10032
Stanford Depression Research Clinic at Stanford University School of Medicine
Stanford, California, 94305
About 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. 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.
Read the 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.
- Conditions
- Treatment Resistant Depression
- Being tested
- Tianeptine Sodium
- Medical subject headings
- Depressive Disorder, Treatment-Resistant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tianeptine SodiumDrug
Also called Tianeurex 12.5 mg
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.
| Study group | Role | What they receive |
|---|---|---|
| Open Treatment | Experimental | All subjects will be treated for 8 weeks of treatment with Tianeptine (Tianeurax 12.5 mg) 3 times a day (9am, 1pm, 5pm). Receives: Drug: Tianeptine Sodium |
What is being measured
The primary outcome is the main question the study is designed to answer.
Hamilton Rating Scale for Depression, 24-item (HAMD-24)
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.
Measured: 8 weeks
Secondary outcomes (2)
Response Rate
Proportion of participants achieving ≥50% reduction in HAMD-24 score from baseline
Measured: 8 weeks
Remission Rate
Proportion of participants achieving HAMD-24 score ≤10 at Week 8
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Jan 2020
- Study start14 Oct 2020
- Primary completion27 Aug 2024
- Study completion27 Aug 2024
Why it stopped: Inadequate recruitment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Treatment Resistant DepressionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jonathan A. Javitch, MD, PhD
- Sponsor type
- University, hospital or other
- Collaborators
- Icahn School of Medicine at Mount Sinai, Stanford University
- Responsible party
- Sponsor-investigator, Jonathan A. Javitch, MD, PhD, New York State Psychiatric Institute
- Investigators
- Alla Landa, PhD, Principal investigator, New York State Psychiatric Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04249596
- Sponsor's protocol ID
- 7944/8436
- Status last verified
- Jan 2026
- First submitted
- 29 Jan 2020
- Last updated
- 23 Jan 2026
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Tianeptine for Treatment Resistant Depression
- ClinicalTrials.gov ID
- NCT04249596
- Acronym / sponsor ID
- 7944/8436
- Conditions
- Treatment Resistant Depression
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Inadequate recruitment
- Enrolment
- 38 participants (actual)
- Lead sponsor
- Jonathan A. Javitch, MD, PhDUniversity, hospital or other
- Collaborators
- Icahn School of Medicine at Mount Sinai, Stanford University
- Study start
- 14 Oct 2020 (actual)
- Primary completion
- 27 Aug 2024 (actual)
- Study completion
- 27 Aug 2024 (actual)
- First posted
- 31 Jan 2020 (actual)
- Results
- Posted 23 Jan 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Open Treatment | Experimental | Drug: Tianeptine SodiumAll subjects will be treated for 8 weeks of treatment with Tianeptine (Tianeurax 12.5 mg) 3 times a day (9am, 1pm, 5pm). |
Who may qualify
- Ages
- 21 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (17 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tianeptine SodiumAlso: Tianeurex 12.5 mgAt 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. | Drug | Open Treatment |
Primary outcome
Hamilton Rating Scale for Depression, 24-item (HAMD-24)
Time frame: 8 weeks
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.
2 secondary outcomes
Response Rate
Time frame: 8 weeks
Remission Rate
Time frame: 8 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jan 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alla Landa, PhD principal investigator
New York State Psychiatric Institute
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Tianeptine Sodium in people with Treatment Resistant Depression, run by Jonathan A. Javitch, MD, PhD at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 23 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Jan 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Hamilton Rating Scale for Depression, 24-item (HAMD-24) (time frame: 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jan 2026.