Tianeptine for Treatment Resistant Depression
Phase: PHASE4
Conditions: Treatment Resistant Depression
Sponsor: Jonathan A. Javitch, MD, PhD

NYSPI 7944
V.12222022
NCT04249596
Tianeptine for Treatment Resistant Depression
1. Introduction
Major depressive disorder (MDD) is a leading cause of disability in adults worldwide 
(~16M patients in US alone). Unfortunately, only ~40% of patients achieve full remission 
following first-line treatment with a selective serotonin reuptake inhibitor (SSRI), creating a 
pressing need for new therapeutic approaches to address treatment-resistant depression. One 
strategy for improving treatment response recognizes the potential for underlying mechanistic 
heterogeneity in MDD and the associated need for focused treatments targeting biologically 
distinct subgroups of MDD patients. Significant evidence suggests dysfunction of endogenous 
opioid signaling pathways as a key biological deficit in some MDD patients. Before the advent of 
electroconvulsive therapy and tricyclic antidepressants in the 1950s, the administration of opioid 
receptor agonists was unsystematically used for treatment of depression. Several case studies and 
small clinical trials have pointed to the efficacy of opioid agonists in treating MDD, with some 
limited evidence in treatment-resistant patients as well. Relatedly, deficiencies in physical and 
emotional pain modulation observed in depressed patients are likely to be linked with underlying 
dysfunction in endogenous opioid signaling. Patients with MDD report physical pain symptoms 
more than twice as often as non-depressed individuals1–3, chronic pain is a significant risk factor for 
developing depression4, and the presence of comorbid pain is a negative prognostic factor for 
antidepressant treatment5. Functional magnetic resonance imaging (fMRI) studies suggest that 
physical pain and social rejection activate common brain regions, such as the dorsal anterior 
cingulate cortex (dACC) and anterior insula (aINS)6,7. Moreover, emotional pain resulting from 
adverse social experiences (e.g., childhood abuse and neglect, romantic rejections, etc.) increases 
vulnerability  to  depression8,9,  and  reduced  pleasure  from  social  interactions  contributes  to 
withdrawal, reduced social support, and the persistence of a depressive episode once it develops10.
We hypothesize that a subgroup of MDD patients with deficient opioid receptor 
signaling will better respond to pharmacological interventions specifically targeting this 
biological mechanism. Studies from our laboratories show that endogenous opioids act at the mu-
opioid receptor (MOR) in response to social rejection and that this response is dramatically blunted 
in depressed individuals.11 In addition, preliminary data from our lab show that healthy individuals 
with high trait rejection sensitivity (RS) also show reduced MOR activation, similar to depressed 
individuals. Notably, approximately one third of all patients with MDD have a “long-standing 
pattern of interpersonal rejection sensitivity”12–14, a common feature in, although not restricted to, 
the “atypical” subtype of MDD15–17. Thus, high RS may represent the behavioral manifestation of 
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underlying deficits in endogenous opioid signaling and blunting of opioid release observed in some 
depressed patients in response to social rejection.11 Indeed, our recent fMRI study showed that 
women with MDD display exaggerated emotional and neural responses to social rejection, 
particularly in the right anterior insula.18 In response to social acceptance, women with MDD 
responded with positive emotions, however neural activity in the nucleus accumbens, a reward 
structure, was dissociated from subjective happiness.18 Since MOR regulates social distress and 
social reward in animals19–28 and humans11,29, interventions targeting this mechanism may be more 
effective than conventional treatments in treating high RS MDD by regulating the neural pathways 
activated during social rejection and social acceptance. 
In this application, we propose to target MOR signaling in depressed patients with 
tianeptine. Tianeptine is an atypical antidepressant that has been used clinically in Europe, Asia, 
and South America since the late 1980s in millions of patients.30-34 Its efficacy in humans is well 
documented, and comparable to, or better, than that of several commonly used classes of 
antidepressants,  including  selective  serotonin  reuptake  inhibitors  (SSRIs)  and  tricyclic 
antidepressants (TCAs).30-40 However, tianeptine’s molecular mechanism of action had remained 
unknown until recently. 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.41,42 Using both genetic knockout and pharmacological inhibition in mouse models 
for the study of depression, we have collected strong evidence that MOR is the direct molecular 
target by which tianeptine exerts its antidepressant effects, an entirely unique mechanism among 
existing antidepressants. Importantly, at clinical doses, tianeptine does not produce euphoria; in 
fact, at 6 times the normal dose, patients reported no euphoria.43 Furthermore, unlike treatment of 
pain by traditional opioid agonists, prolonged occupancy of the receptor is not required for the 
antidepressant effect. Instead, much like the hypothesized pulsatile and time-limited action of 
endogenous opioids in response to social rejection and acceptance, tianeptine-induced MOR 
agonism sets in place a signaling cascade that leads to lasting physical changes in dendritic 
structure in key brain circuits.44,45 Of note, tianeptine was never approved for clinical use in the US, 
but has been used safely and widely throughout Europe, Asia, and South America for decades.
The major goals of this project are (1) to define the relationship between opioid signaling 
deficits and response to tianeptine treatment, (2) to develop a comprehensive assessment battery 
capable of identifying endogenous opioid signaling deficits to explore biological heterogeneity in 
the MDD population, and (3) ultimately to improve the response rate compared to standard of care 
in a subgroup of MDD patients selected based on biomarkers of opioid signaling deficiencies.
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2. General Design
2.1. Study sites and organizational structure.
The studies proposed in this application 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. As the lead institution, NYSPI will be 
responsible for managing the finances of the project and overseeing database management, and 
regulatory/reporting functions. Jonathan Javitch, MD, PhD at Columbia University and NYSPI is 
the overall study PI and maintains responsibility for study-wide decisions involving study 
logistics and the scientific direction of the project.
We have chosen to recruit subjects and perform all assessments except for neuroimaging 
procedures at the two sites (N=24 at each site for overall study N=75, 28 already entered), which 
will increase the rate of participant enrollment, ensure that recruitment goals are met, and 
enhance the generalizability of the sample. Structural and task-based magnetic resonance 
imaging (MRI) will be performed solely under Dr. Landa’s direction at NYSPI in order to 
maintain internal validity of the data set. MSSM subjects will be transported to NYSPI to 
complete neuroimaging procedures as described below.
2.2. Subject recruitment and screening procedures.
Recruitment will proceed in parallel at each study site by means of (1) screening 
individuals who directly contact the clinical programs at MSSM and SUSM, (2) referral from 
clinicians in other disciplines at the component institutions participating in this project, and (3) 
outreach to the communities surrounding MSSM and SUSM. We also promote recruitment of 
under represented  minority subjects by anticipating and working to eliminate barriers to research 
participation. Promotional materials at each component clinic allay these concerns by explaining 
how our studies are designed to mitigate and overcome these barriers to participation in research 
studies.
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Potential subjects will be evaluated by remote and/or in-person meetings. Those who decide to 
participate by signing informed consent will have an evaluation inclusive of a clinical interview 
by a study clinician, structured diagnostic interview, and completion of standardized rating scales 
(trained rater) in order to document eligibility. Eligible subjects will have further documentation 
of vital signs, medical history urine drug screen, CBC, chemistries and electrolytes, thyroid 
profile, urine analysis, standing/supine systolic/diastolic BP, and ECG. Female participants will 
undergo urine pregnancy testing to confirm that they are not pregnant prior to drug initiation and 
will be instructed to use effective birth control during the study, such as condoms, IUDs, oral 
contraceptives, or depot contraceptives. Participants also will be scheduled for further baseline 
testing as described below. 
2.3. Imaging procedures.
Pre- and post-treatment brain MRI for subjects enrolled at MSSM will be performed on 
each subject using a 3T Siemens Prisma scanner located at NYSPI. Participants from the MSSM 
site will have transportation arranged and paid at the study’s expense.  Subjects will be 
compensated for their time spent in transit in addition to regular compensation for MRI 
procedures.
At the start of the scanning session, a 3-Plane localizer (scout) will be acquired to 
determine patient position. Subjects will then receive (1) T1-weighted 3D for volumetric analysis 
and coregistration of functional MRI data, (2) EPI scan during Thermal pain sensitivity task, (3) 
EPI scan during Social Feedback task, and (4) EPI scan while Resting. For the MRI procedures, 
participants are instructed to lie as still as possible within the magnet. The MRI scan is 
completed in one session lasting for a total of 60 minutes. All precautions and protections are 
given to the participant to ensure that they are as safe and as comfortable as possible. The 
participant is given a squeeze ball to terminate the scan at any time. Conducting these procedures 
will be an accredited Magnetic Resonance Technologist and one member of the research staff 
(Bachelor’s Level or Higher). 
MRI data will be analyzed with Statistical Parametric Mapping (SPM).  We will conduct 
a whole-brain analysis in a voxel-by-voxel brain-wide search as well as hypothesis-driven region 
of interest (ROI) analysis (Bonferroni-corrected alphas for multiple VOIs) to examine brain areas 
(e.g., amygdala, nucleus accumbens, ventrolateral prefrontal cortex, anterior cingulate cortex, 
anterior insula) previously shown to regulate responses to physical pain as well as positive and 
negative social stimuli.  Statistical parametric maps are obtained using whole-brain image 
subtraction routines with the images warped to standardized space.
Thermal
 
  Pain
 
  Sensitivity
 
  Task
 
 : Thermal stimulations will be delivered to left volar 
forearm using an MRI-safe delivery system. Series of 10 second stimuli will be administered, 
each followed by an 18-22 seconds rest period. We will administer series of moderately painful 
temperatures (one subjectively rated as level 6 on a 0-10 VAS scale and one standard temperature 
of 45o) in a semi-random order (random for participant, same order across subjects). With a 
calibration procedure performed before the MRI,1 we will choose the temperature to administer 
in fMRI  on a participant-by-participant basis to be sure that the subjective pain intensity is 
constant across participants. During the task itself, participants are asked to stare at a fixation 
cross during each trial and focus on the sensations elicited by the somatic stimulus. Participants 
are then instructed how to rate their after each trial trial using ten-point VAS scales . In the 
7

second part of pain task, instead of resting between pain stimuli participants are asked to interact 
with other by playing a computer ball-tossing game.
Social feedback task: Prior to the scanning session, all subjects will complete an “online 
profile” (e.g., gender, age, birthdate, race/ethnicity, orientation, major/occupation, hobbies, 
personal qualities, years of education, etc.) and provide a digital photo of her/himself prior to 
rating profiles of others.  If subjects do not have a photo available or prefer, they may have a 
digital photo taken during the interview.  All subjects then complete online ratings of personal 
profiles from a collection of over 500 men and women with whom they would be most interested 
in forming a close personal relationship. Subjects will be informed that this task is a simulation, 
and that others’ ratings of the subject are not “real.” During the scanning session, subjects are 
presented with their own picture along with a picture of a highly rated profile, along with 
feedback that they were liked (acceptance trial), not liked (rejection trial), or that others were 
undecided or had not yet rated them (neutral trial). Questionnaires will be given before, during, 
and/or after the task to assess cognitive and emotional states. For questionnaires, answer choices 
are presented on Likert scale (e.g., 5 discrete choices), or a visual analogue scale (e.g., a sliding 
scale), verbally, on paper, or on a computer. 
2.4. Comprehensive assessment of physical and emotional pain functioning.
The hypothesis under investigation in this study is that a subgroup of depressed 
outpatients experience brain opioid signaling dysfunction, which manifests behaviorally as 
increased physical and emotional pain sensitivity, and will be predictive of greater response to 
tianeptine (i.e., due to its mu-opioid receptor agonism). In addition to the imaging procedures 
described above, this hypothesis will be further studied by having participants complete a 
assessment battery testing pain functioning at baseline and study endpoint, in addition to further 
weekly assessments of selected measures. 
All subjects will complete the baseline evaluation, which includes psychiatric assessments 
(HARS, STAI, IDS-SR, CGI, MMSE), physical pain tests (Thermal Sensitivity Test, BPI, 
Physical and Psychological Pain Scale), as well as emotional pain and interpersonal wellbeing 
tests (ARSQ, C-SSRS, Psychache scale, Perceived Stress Reactivity Scale (PSRS), Perceived 
Stress Scale, Shyness and Sociability Scale, Reaction to Implied Rejection Measure, Hurt 
Feelings Questionnaire, Multidimensional Scale of Perceived Social Support)
2.5. Summary of visit schedule and other study assessments.
As described above, at Screening, patients who decide to participate by signing informed consent 
will undergo a psychiatric clinical interview, and eligibility is determined by assessments with 
the Structured Clinical Interview Diagnostic for DSM 5 (SCID) and 24-item Hamilton Rating 
Scale for Depression (HRSD). Eligible subjects will complete screening laboratory tests and 
those currently taking other antidepressant medications will be tapered off under the supervision 
of the research staff according to standard clinical practice or by the doctor currently prescribing 
the medication. There will be a 5 day wash-out period from the time the previous antidepressant 
has been stopped before tianeptine is started, 3 weeks if the previous antidepressant was a 
monoamine oxidase inhibitor and 4 weeks if the antidepressant was fluoxetine. For participants 
requiring an antidepressant taper, the screening psychiatric assessments will be repeated post-
8

taper to confirm inclusion criteria are still met. Eligible subjects will then complete the 
remainder of the baseline evaluation, which includes the Hamilton Anxiety Rating Scale 
(HARS), State Trait Anxiety Inventory (STAI), Inventory of Depressive Symptomatology—Self 
Report (IDS-SR), Clinical Global Impressions (CGI) Severity and Improvement, Mini Mental 
State Examination (MMSE), physical pain tests (BPI), emotional pain tests (ARSQ, C-SSRS, 
Psychache scale), Drug Abuse Screen Test (DAST), and Michigan Alcohol Screen Test 
(MAST). Finally, for patients who are willing to participate, whole-blood samples will be drawn 
and used to screen for genetic polymorphisms in the genes for the mu-opioid receptor (e.g., 
A118→G), oxytocin receptor, vasopressin receptor 1A, and monoamine oxidase A, all of which 
have been shown to moderate behavioral and neural responses to rejection. Blood samples will 
be stored for future analysis if other potential genetic biomarkers are later identified.
Following screening and baseline measures, subjects will undergo MRI scanning, which is 
performed prior to Week 0. At Week 0,  tianeptine medication will be initiated at 12.5 mg po tid. 
The first dose of tianeptine 12.5 mg is given at the Week 0 appointment under the supervision of 
study staff so that initial response can be observed. Subjects will be instructed not to consume 
any food for at least 3 hours prior to their appointment to control any food effect on tianeptine’s 
pharmacokinetics. Orthostatic blood preasure and heart rate will be measured before tianeptine 
administration, subjects will be observed for a period of 1 hour. 
Subjects return at Weeks 1, 2, 3, 4, 5, 6, 7, and 8 (+/– 2 days) for depression follow-up visits 
and complete the HRSD, CGI Severity and Improvement, IDS-SR, and Structured Pill Count 
Interview. At baseline, week 4 and week 8 subjects will also repeat the following tests: HARS, 
VAS Physical and Psychological Pain Scale. Perceived Stress Reactivity Scale (PSRS), 
Perceived Stress Scale Psychache Scale, UCLA Loneliness Scale, Shyness and Sociability. 
Reaction to Implied Rejection Measure. Hurt Feelings Questionnaire. Adult Rejection Sensitivity 
Questionnaire, Multidimensional Scale of Perceived Social Support, Brief Pain Inventory (BPI).. 
All baseline measures will be repeated at study endpoint (Week 8), including a post-treatment 
MRI scanning visit at NYSPI. 
Revised table of procedures and timetable is shown below:
9

Screening
Baseline 
w0
w1 w2 w3 w4 w5 w6 w7
End of Tx 
w8
Informed Consent
x
Inclusion/Exclusion
x
Vital Signsa
x
x
x
x
ECG
x
x*
x
Clinical Labsb
x
x
x
Liver Function Test
x
x
x
Blood Genomics
x**
x**
x**
Urine Pregnancy Testc
x
x
x
Urinalysis
x
Drug Screening
x
MRI Eligibility Screener
x
x
x
Facial Recognition Task (csv)
x
x
Thermal Calibration (csv)
x
x
Imagery Training, fMRI instructions, practice
x
x
Localizer/Structural MRI/Field Map
x
x
Social Feedback Task (csv)
x
x
Resting State
x
x
Thermal Pain Task (csv)
x
x
Visual Analogue Scale-Body Pain
x
x
Social Feedback Follow-Up
x
x
Study Medication Dispensation
x         
x
x    
x
x
Demographics/Profile Ratings
x
x
Taper Antidepressant Medicationd
x
ATHF
x
Medical History
x
SCID
x
MMSE
x
Clinical/Medication Progress Note
x
x
x
x
x
x
x
x
x
x
Pill Count
x
x
x
x
x
x
x
x
AE Assessment
x
x
x
x
x
x
x
x
x
HRSD 24-item
x
x
x
x
x
x
x
x
x
x
HARS
x
x
x
CGI S/I
x
x
x
x
x
x
x
x
x
x
CSSR-S
x
x
Social Feedback Profiles rating 
x
x
IDS-SR
x
x
x
x
x
x
x
x
x
VAS Physical and Psychological Pain Scale
x
x
x
x
x
Perceived Stress Reactivity Scale (PSRS)
x
x
x
Perceived Stress Scale
x
x
x
Psychache Scale
x
x
x
UCLA Loneliness Scale
x
x
x
Shyness and Sociability
x
x
x
Reaction to Implied Rejection Measure
x
x
x
Hurt Feelings Questionnaire
x
x
x
Adult Rejection Sensitivity Questionnaire
x
x
x
Multidimensional Scale of Perceived Social Support
x
x
x
BPI (pain)
x
x
x
PBI (parent bonding)
x
Childhood Trauma Questionnaire
x
Faces Discrimination Task
x
x
MRI scan (structural, SFT, Resting State, Pain Task)
x
x
Procedures and Assessments
Timepoints
a Vital signs include blood pressure and pulse
b Clinical labs include CBC, Chem 7, TSH, Cholesterol, B12, and Folate
c Pregnancy test will be performed on women of child bearing potential
d Washout period only for subjects on other antidepressant medication
10

* Assessment may be repeated based on clinician discretion; ** Optional
2.6. Tianeptine administration.
Following screening and baseline testing, all subjects will begin tianeptine 12.5 mg three 
times daily (total daily dose 37.5 mg/day) for a total duration of 8 weeks of treatment. Subjects 
who develop side effects that prevent them from taking the  the full three times daily dosage will 
have their dosage reduced to tianeptine 12.5 mg twice daily, and those unable to tolerate at least 
25 mg/day dosing will be dropped out of the study. Based on the extensive experience of 
clinicians in Europe, where tianeptine is approved for the treatment of depression, we expect this 
dosage regime to be well-tolerated. During the study, concomitant use of other antidepressants, 
antipsychotics, anticonvulsants, central nervous system stimulants, anti-addiction agents, and 
cognitive enhancers are prohibited, with the exception of small doses of benzodiazepines (≤ 2 
mg lorazepam equivalents per day), which will be permitted for anxiety or insomnia. 
          Medication was purchased from Neuraxpharm in Germany and shipped to the NYSPI 
pharmacy where it is stored. Medication is shipped to the MSSM pharmacy, where it is packaged 
and prescribed for MSSSM patients in containers containing a 2 week supply ( 50 blister packed 
12.5 mg pills – enough for two weeks plus an additional pills alloatted in case of a delayed visit ) 
at the 0, 2,4, and 6 week visits and 20 blister packed pills for the final taper. Medication is 
shipped to the Stanford Depression Research Clinic in the same quantities and it is dispensed to 
patients using the same procedures as atMSSM. At each in person visit, the subject should return 
the bottle, and the number of remaining pills will be counted and recorded to monitor 
compliance.
2.7. Early discontinuation criteria and handling of emergencies.
The risk of non-response to tianeptine during the study period is addressed by having 
close clinical follow up of study subjects and stringent withdrawal criteria. These criteria are (1) 
participant withdraws his or her consent; (2) significant clinical worsening in the judgment of the 
study clinician; (3) a CGI-Improvement rating7 by the study clinician of 6 (worse) or 7 (much 
worse) for 2 consecutive visits; or (4) development of significant side effects or an adverse event 
grade 3 or higher. Any subject meeting any of these criteria will be withdrawn from the study 
and treated clinically. Furthermore, subjects may be withdrawn if they repeatedly miss scheduled 
appointments. If clinical worsening necessitates more intensive treatment, appropriate clinical 
care will be given but if possible the patient will still complete the ongoing assessments and final 
imaging visits. 
Should a subject express suicidal ideation at any time during a study visit, the study 
clinician will be contacted immediately to assess the subject and to determine the appropriate 
course of action. Options for addressing suicidal ideation will include contacting the individual’s 
mental health caregiver (if available), referring for urgent (same day) evaluation and treatment in 
an outpatient clinic, or emergency room evaluation and hospitalization. Similar practices will be 
used for other emergencies, including but not limited to psychosis, homicidal or violent thoughts, 
or an acute change in a subject’s physical status.
2.8. Tianeptine taper and post-protocol treatment.
Once all study assessments are completed, subjects will be tapered off of tianeptine 
medication. Subjects will have their dosage reduced to 12.5 mg twice daily for two weeks, then 
12.5 mg once daily for two weeks, and then tianeptine will be discontinued. Subjects will be 
assessed every two weeks in this post-protocol phase, with continuation of HRSD and CGI rating 
11

scales. Appropriate clinical options will be discussed with any subject demonstrating worsening 
HRSD (≥ 16 on 24-item scale) or CGI (Improvement score ≥ 5 or Severity score ≥ 4 for two 
consecutive weeks) scores, most likely including initiation of FDA-approved antidepressant 
medication. 
2.9 References
1) Wager TD, Rilling JK, Smith EE, et al. Placebo-induced changes in FMRI in the anticipation 
and experience of pain. Science 2004; 303:1162-7.2) Roy M, Shohamy D, Daw N, et al. 
Representation of aversive prediction errors in the human periaqueductal gray. Nature Neurosci 
2014; 17:1607–1612.
3) Kennedy DL, Kemp HL, Ridout D, et al. Reliability of conditioned pain modulation: a 
systematic review. Pain 2016; 157:2410–2419. 
4) Berenson KR, Gyurak A, Ayduk O, Downey G, Garner MJ, Mogg K et al. Rejection 
sensitivity and disruption of attention by social threat cues. J Res Personal 2009; 43: 1064–1072.
5) Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry 2011; 168: 1266–1277.
6) Holden RR, Mehta Karishma, Cunningham EJ, McLeod LD. Development and preliminary 
validation of a scale of psychache. Can J Behav Sci 2001; 33: 224–232.
7) Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US 
Department of Heath, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and 
Mental Health Administration; 1976.
3. Subject Selection and Withdrawal
3.1 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. 
3.2 Exclusion Criteria
1) Any history of opioid-use disorder
12

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)
4. Primary Study Endpoints
1. HRSD change from Week 0 to Week 8
4.1 Secondary Study Endpoints
1. Response rate to tianeptine (baseline HRSD decreases by ≥ 50%) 
2. Remission rate to tianeptine (final HRSD ≤ 7)
3. Change in VAS pain scores from Week 0 to Week 8
4. Change in emotional pain as measured by the ARSQ from Week 0 to Week 8
4.2 Primary Safety Endpoints
The primary safety endpoint is:
13

Rate of serious adverse events (SAEs):
All SAEs will be assessed by a study physician to determine whether the relationship to the 
study procedures or treatment is considered to be likely, unlikely or  unknown. 
5. Statistical Plan
5.1 Sample Size Determination
With total sample size of 75 subjects, we have >80% power to detect an effect size for a 
change in HRSD (from week 0 to week 8) of at least (Cohen’s) d = 0.33 (small-medium), using a 
2-sided test with a 5% significance level. With this sample size we can construct 95% confidence 
intervals for the response/remission rates that are no more than 25 percentage points wide. For 
our subgroup analyses to examine the hypothesis that baseline pain (physical or emotional) will 
differentially relate to improvement in depression, assuming a median split (low/high, n = 37/38) 
for a given physical or emotional pain battery score, we have >80% power to detect an effect size 
for a difference in change in HRSD (low group vs. high group) of at least d = 0.66 (medium-
large), using a 2-sided test with a 5% significance level. Similarly, we have >80% power to 
detect differences in proportions of responders/remitters between the pain groups that are at least 
30 percentage points. As an example, if depression response/remission is 10% in the low pain 
group and 40% in the high pain group, we have 86% power to find this statistically significant at 
the 5% significance level.
5.2 Statistical Methods
Descriptive analyses for all variables collected at all time points will be conducted both 
overall and by study site. If differences are found between the study sites on outcomes of interest, 
then study site will be adjusted for in the analyses. For the intent-to-treat sample (i.e. those who 
started on drug at week 1 regardless of compliance across the 8 weeks), we will report 
proportions of responders and remitters and mean changes in HRSD, VAS pain score, and ARSQ 
from week 0 to week 8. In addition to these point estimates, we will report the corresponding 
95% confidence intervals. Similar analyses will be done on the sample of completers (i.e. those 
who complied with drug administration across all 8 weeks based on pill counts of at least 80%).
To examine the hypothesis that baseline pain level will be predictive of response to 
tianeptine, we will further investigate whether any single baseline pain battery score can be used 
to construct subgroups of subjects showing greater response to tianeptine. Based on the 
distribution of a given pain battery score and preliminary exploratory bivariate modelling, we 
will dichotomize the pain score (low/high) and compare response/remission rates and change 
scores for HRSD between the groups corresponding to low and high pain battery score. We will 
14

report effect sizes corresponding to differences in response/remission rates and differences in 
HRSD change scores. Exploratory analyses will employ multivariable logistic (for 
response/remission outcomes) and linear (for HRSD change score) regression to investigate 
whether combinations of baseline pain scores can be used to identify subgroups who will show 
greater response to tianeptine. Additional analyses will employ multivariable logistic and linear 
regression to investigate associations between baseline neuropsychiatric and/or MRI measures 
and remission/response or HRSD change score. To take advantage of the fact that HRSD and 
TESS are collected at each study visit (8 post-baseline measures), we will also employ linear 
mixed effects models to investigate the effects of each baseline pain battery score on HRSD and 
TESS over time.
5.3 Subject Population(s) for Analysis
Subjects will be adult outpatients with treatment-resistant MDD who are without 
contraindications for neuroimaging procedures or tianeptine administration.
6. Safety and Adverse Events
6.1 Definitions
Adverse Event: Adverse event means any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction. An adverse event 
or suspected adverse reaction is considered "life-threatening" if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Serious Adverse Event: Serious adverse event or serious suspected adverse reaction. 
An adverse event or suspected adverse reaction is considered "serious" if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
15

Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
Unexpected adverse event or unexpected suspected adverse reaction. An adverse event or 
suspected adverse reaction is considered "unexpected" if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current application, as amended. For example, 
under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) 
if the investigator brochure listed only cerebral vascular accidents. "Unexpected," as used in this 
definition, also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
Adverse Event Reporting Period: The study period during which adverse 
events must be reported is normally defined as the period from the initiation 
of any study procedures to the end of the study treatment followup. For this 
study, the study drug follow-up is defined as 24 hours following the last 
administration of study drug (or the end of the study for those who must stop 
tianeptine but continue with the assessments).
Preexisting Condition: A preexisting condition is one that is present at 
the start of the study. A preexisting condition will be recorded as an adverse 
event if the frequency, intensity, or the character of the condition worsens 
during the study period.
General Physical Examination Findings: At screening, any clinically 
significant abnormality will be documented. At the end of the study, any new 
clinically significant findings/abnormalities that meet the definition of an 
adverse event will also be recorded and documented as an adverse event.
Abnormal Laboratory Values: A clinical laboratory abnormality will be 
documented as an adverse event if any one of the following conditions is 
met: (1) the laboratory abnormality is not otherwise refuted by a repeat test 
to confirm the abnormality, (2) the abnormality suggests a disease and/or 
organ toxicity, (3) the abnormality is of a degree that requires active 
management; e.g. change of dose, discontinuation of the drug, more 
frequent follow-up assessments, further diagnostic investigation, etc.
16

Hospitalization, Prolonged Hospitalization or Surgery: Any adverse event 
that results in hospitalization or prolonged hospitalization will be 
documented and reported as a serious adverse event unless specifically 
instructed otherwise in this protocol. Any condition responsible for surgery 
should be documented as an adverse event if the condition meets the 
criteria for and adverse event. Neither the condition, hospitalization, 
prolonged hospitalization, nor surgery are reported as an adverse event in 
the following circumstances: (1) Hospitalization or prolonged hospitalization 
for diagnostic or elective surgical procedures for a preexisting condition, (2) 
hospitalization or prolonged hospitalization required to allow efficacy
measurement for the study, (3) hospitalization or prolonged hospitalization 
for therapy of the target disease of the study, unless it is a worsening or 
increase in frequency of hospital admissions as judged by the clinical 
investigator.
Known Side Effects of tianeptine:
Tianeptine is generally well tolerated and severe side effects are rare.1-5 Tolerability in comparative 
clinical trials has been generally found to be better than tricyclic antidepressants and comparable to 
selective serotonin reuptake inhibitors.1-5 Commonly reported side effects with an incidence 
between 1 and 10% include the following:1-6
Gastrointestinal: nausea, vomiting. flatulence, constipation, abdominal pain, dry mouth, loss of 
appetite
Psychiatric and Central Nervous System: headache, dizziness, altered dreaming, drowsiness, 
insomnia, presyncope, tremors
Cardiovascular: palpitations, chest pain, hot flashes, tachycardia
Respiratory: difficulty breathing
Musculoskeletal: muscle pain, lower back pain
General: feeling of weakness, feeling of lump in the throat
6.2 Recording of Adverse Events
At each contact with the subject, the investigator will seek information 
on adverse events (AEs) by specific questioning and, as appropriate, by 
examination. Information on all adverse events will be recorded immediately 
in the source document. All clearly related signs, symptoms, and abnormal 
17

diagnostic procedures results will be recorded in the source document. All 
adverse events occurring during the study period will be recorded. The 
clinical course of each event will be followed until resolution, stabilization, or 
until it has been determined that the study treatment or participation is not 
the cause. Serious adverse events that are still ongoing at the end of the 
study period will be followed up to determine the final outcome. 
6.3 Reporting of Serious Adverse Events
6.3.1 IRB Notification by Investigator
Each SAE will be reported by the site within 24 hours to their IRB as 
well as to the IND sponsor by email to: jaj2@cumc.columbia.edu. The site PI 
together with the IND sponsor will make the determination as to whether an 
incident, experience or outcome is likely to be the result of study procedures 
or treatment. The investigator must conclude in the SAE Report whether the 
protocol and/or consent form(s) should be modified as the result of the SAE. 
If the protocol and/or consent document(s) requires a revision, a modification 
must be submitted. At the time of continuing review of a protocol by each 
site’s IRB, the site PI will submit a summary of all SAEs that occurred during 
the review period and since the beginning of the study, with a copy to the 
IND sponsor. 
6.3.2 FDA Notification by Sponsor
The IND sponsor shall notify the FDA by telephone or by facsimile 
transmission of any unexpected fatal or life-threatening experience 
associated with the use of the drug as soon as possible but no later than 7 
calendar days from the investigator’s original
receipt of the information. All other events that are considered to be serious, 
unexpected and possibly related to the study drug will be reported to the 
FDA within 15 calendar days. In addition, the IND sponsor will provide a summary of all 
SAEs in the annual reports submitted to the FDA.
6.4 Drug Related Risks
Tianeptine is generally well tolerated and severe side effects are rare.1-5 Tolerability in comparative 
clinical trials has been generally found to be better than tricyclic antidepressants and comparable to 
selective serotonin reuptake inhibitors.1-5 Commonly reported side effects with an incidence 
between 1 and 10% include the following:1-6
Gastrointestinal: nausea, vomiting. flatulence, constipation, abdominal pain, dry mouth, loss of 
appetite
18

Psychiatric and Central Nervous System: headache, dizziness, altered dreaming, drowsiness, 
insomnia, presyncope, tremors
Cardiovascular: palpitations, chest pain, hot flashes, tachycardia
Respiratory: difficulty breathing
Musculoskeletal: muscle pain, lower back pain
General: feeling of weakness, feeling of lump in the throat
Extremely rarely, hepatotoxicity may occur, which is evidenced by increased liver enzymes 
and is fully reversible on drug withdrawal.7-9 Such liver toxicity appears to result from an 
immunoallergic response to the drug. To our knowledge, only 3 such cases have been reported in 
the literature. In contrast, the hepatic safety of tianeptine appears excellent in the vast majority of 
patients, even in instances of excessive consumption during abuse. For instance, a patient who 
became addicted to tianeptine and consumed doses of up to 1875 mg/day for over 5 months 
experienced no changes in hepatic toxicology parameters.10  Liver function tests will nonetheless 
be repeated at Week 4 to insure that levels are stable.
When used at the usual dosage of 37.5 mg/day, there is no development of physical or 
psychological dependence on tianeptine and no notable withdrawal symptoms on treatment 
cessation.1-5 Rarely (1-3 per 1000)11, abuse of tianeptine or dependence on the drug (when used at 
supratherapeutic doses) may occur. To account for this risk, we have planned for abuse risk 
mitigation by excluding patients with a history of opioid abuse, limiting drug distribution to 9-day 
courses provided at weekly clinical visits, and monitoring compliance at each clinical visit.
Drug
 
  Dependence
 
  and
 
  Abuse
 
  Potential
 
 : 
Tianeptine’s activity is a full agonist of the mu-opioid receptor (MOR; its hypothesized 
mechanism of action) and the use of the drug in clinical practice has been safe. The tianeptine 
dose (12.5 mg, t.i.d.) that is used clinically for depression is in the sub-euphoric range, that is, the
drug does not induce notable rewarding or psychoactive (other than anti-depressant) effects at 
this dose. The clinically used dose is also not associated with physical or psychological 
dependence after discontinuation, even after prolonged treatment. Therefore, there appears to be 
a significant safety margin between the therapeutic dose and the dose necessary to induce acute 
rewarding or other psychoactive effects. In a controlled trial of abuse liability in healthy 
volunteers, a single supratherapeutic dose of tianeptine (75 mg) did not separate from placebo in
any subscale of the Addiction Research Center Inventory, in contrast to the positive control 
methylphenidate (40 mg), suggesting limited, if any, abuse or addiction liability at typical 
therapeutic doses. Consistent with this finding, abuse of tianeptine was not observed during 
treatment of patients previously addicted to opioids, suggesting that in most cases the clinical 
dose is too low to reinitiate drug seeking behavior in patients with a history of substance abuse. 
Using incidence of “doctor shopping”   as an indicator of aberrant use, another study found that 
19

tianeptine abuse potential is comparable to or slightly lower than that of benzodiazepines, drugs 
widely used in clinical practice despite recognized   modest abuse potential. Accordingly, the 
risk-benefit ratio for use of tianeptine in psychiatric indications is favorable, especially for 
treatment-resistant depression, where standard-of-care treatments have already failed.Despite 
this occasional incidence of serious misuse, acute tianeptine overdose or chronic abuse are not 
often associated with severe complications or fatalities. In a single ascending dose study in 
healthy volunteers, the high dose of 337.5 mg elicited only transient adverse effects of nausea, 
vomiting, and sedation.
Accordingly, there is expected to be limited risk of dangerous overdose in the present 
study. Similarly, most chronic users of high-dose tianeptine do not experience serious 
toxicological complications (notably, no hepatotoxicity except in extremely rare cases) other 
than a withdrawal syndrome on discontinuation. In a long-term treatment study, 7 patients who 
attempted suicide by tianeptine overdose (dose of 150-500 mg, concomitant with alcohol or 
other psychotropic drugs) survived with favorable outcomes. Overdose has   also been reported 
to be reversible with naloxone, consistent with agonist activity at MOR. To our knowledge, 
only 5 overdose deaths following tianeptine ingestion have been reported in the literature. In  
one case, tianeptine was the only intoxicant identified. However, the other cases were 
complicated by the identification of other psychoactive substances in the circulation of the 
decedents (one in combination with tramadol, one in combination with alprazolam, one a 
suicide in combination with alcohol, and one a suicide in combination with clomipramine and 
hydroxyzine).
To minimize risk patients with any history of opioid-use disorder or any history of 
moderate non-opioid (except nicotine) substance use disorder are excluded. Medication is 
distributed biweekly with a two week supply given and unused pills are collected at each 
in-person visit.
References
(1) McEwen, B. S.; Chattarji, S.; Diamond, D. M.; Jay, T. M.; Reagan, L. P.; Svenningsson, P.; 
Fuchs, E. The Neurobiological Properties of Tianeptine (Stablon): From Monoamine Hypothesis 
to Glutamatergic Modulation. Mol. Psychiatry 2010, 15 (3), 237–249.
(2) Kasper, S.; McEwen, B. S. Neurobiological and Clinical Effects of the Antidepressant 
Tianeptine. CNS Drugs 2008, 22 (1), 15–26.
(3) Wagstaff, A. J.; Ormrod, D.; Spencer, C. M. Tianeptine: A Review of Its Use in Depressive 
Disorders. CNS Drugs 2001, 15 (3), 231–259.
(4) Preskorn, S. H. Tianeptine: A Facilitator of the Reuptake of Serotonin and Norepinephrine as 
an Antidepressant? J. Psychiatr. Pract. 2004, 10, 323-330.
20

(5) Wilde, M. I.; Benfield, P. Tianeptine: A Review of its Pharmacodynamic and Pharmacokinetic 
Properties, and Therapeutic Efficacy in Depression and Coexisting Anxiety and Depression. Drugs 
1995, 49 (3), 411-439.
(6) See the Summary of Product Characteristics (SmPC) included with this submission as 
Attachments E (original German) and F (English translation).
(7) Balleyguier, C.; Stérin, D.; Ziol, M.; Trinchet, J. C. Acute Mixed Hepatitis Caused by 
Tianeptine [Article in French]. Gastroenterol. Clin. Biol. 1996, 20, 607-608.
(8) Le Bricquir, Y.; Larrey, D.; Blanc, P.; Pageaux, G. P.; Michel, H. Tianeptine – An Instance of 
Drug-Induced Hepatotoxicity Predicted by Prospective Experimental Studies. J. Hepatol. 1994, 
21, 771-773.
(9) Rifflet, H.; Vuillemin, E.; Rifflet, I.; Oberti, F.; Pilette, C.; Calès P. Acute Painful and Febrile 
Hepatic Involvement Related to Ingestion of Tianeptine [Article in French]. Gastroenterol. Clin. 
Biol. 1996, 20, 606-607.
(10) Vandel, P.; Regina, W.; Bonin, B.; Sechter, D.; Bizouard, P. [Abuse of Tianeptine. A Case 
Report]. Encephale. 1999, 25 (6), 672–673.
(11) “Stablon 12.5 mg, coated tablet,  Re-assessment of Actual Benefit at the request of the 
Transparency  Committee”  Haute  Authorité  de  Santé;  Transparency  Committee  Opinion; 
December 5th, 2012.
6.5 Stopping Rules
Refer to Section 2.7
6.6 Medical Monitoring
Adverse events will be documented in the study database. Notification of 
SAEs to the IRB and FDA will take place as described in Section 6.3. All 
adverse events will be reviewed and assessed by the study investigators at 
each site, and the SAEs from each site will be reviewed by the IND sponsor.
7. Data Handling and Record Keeping
7.1 Confidentiality
All study data will be collected and stored in compliance with all 
applicable guidelines regarding patient confidentiality and data integrity. All 
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subject research data will be coded with subject ID number. All laboratory 
and clinical information obtained from this research will be maintained in 
locked offices and will be accessible only to the main investigators of this 
project. The REDCAP-based electronic database used during the trial is 
secure and password protected. Subjects’ information will not be discussed 
in any form in the presence of other subjects or non-study personnel. 
Subjects will only be referred to by their subject unique ID number in all 
study documents. For every research subject, relevant clinical information is 
documented on electronic case report forms and source documents and 
stored in the secure electronic database or in a double locked area. All study 
records will be maintained for a minimum of 7 years. If requested, the IRB 
and FDA will have full access to all study records. 
7.2 Source Documents
Source data is all information, original records of clinical findings, 
observations, or other
activities in a clinical trial necessary for the reconstruction and evaluation of 
the trial. Examples of these original documents and data records include: 
research clinic charts, laboratory data, 
pharmacy dispensing records, MRI scans, and results of physiologic testing. 
7.3 Case Report Forms
The study will utilize both paper case report forms (CRFs) and an electronic 
data capture system (EDC) Acquire EDC TM for data collection (see below). 
Paper case report forms and supporting source documents will be filed in the 
subject charts and will be the basis for data entered into Acquire. All data 
requested on the paper CRFs  must be recorded, and all missing data must 
be explained. If a field on the paper CRF is left blank because the procedure 
was not done or the question was not asked, “N/D” will be written. If the item 
is not applicable to the individual case, “N/A” will be written. All entries will 
be printed legibly in black ink. If any entry error has been made, to correct 
such an error, a single straight line will be drawn through the incorrect entry 
and the correct data entered above it. All such changes will be initialed and 
dated. 
The study statisticians will make regular reports to investigators on accrued 
data, identify unusual or unexpected data points, and request that they be 
confirmed or corrected. The data will be queried and monitored  in 
accordance with Attachment L, the “Study Monitoring Plan,” with a frequency 
specified in the plan and based on study progress and need.
The Innovative Clinical Research Solutions (ICRS) group at the Nathan S. 
Kline Institute for Psychiatric Research (NKI) will design the eCRFs to capture 
all required protocol information and will host the database. ICRS personnel 
have been providing databases and management support for clinical 
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research studies for over 35 years and have conducted such functions for 
numerous studies funded by the National Institute of Mental Health (NIMH) 
and by pharmaceutical companies (FDA-regulated IND studies) . 
 
The primary objectives of the ICRS data management methodology are to 
insure the completeness and integrity of all study data. To accomplish these 
objectives, ICRS will provide a comprehensive data collection methodology 
combined with strong planning, control, and coordination with study research 
staff. ICRS will develop all study electronic Case Report Forms (eCRFs) to 
standardize data collection. A comprehensive web-based data acquisition 
and management system, Acquire, will be programmed to process, edit and 
store all study data in a centralized database. Acquire will be developed to 
meet the specific requirements of the study. ICRS personnel will implement 
rigorous data editing/validation using the Acquire system to insure the 
highest possible level of data accuracy. 
A description of the Acquire EDC system is contained in Attachment M.
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Data
 
  and
 
  Safety
 
  Monitoring
 
  Board
 
  (DSMB)
 
 
A Data and Safety Monitoring Board (DSMB) has been created as an independent body 
charged with ensuring that the safety of study subjects is protected and that the scientific 
goals of the study are being met.  To support those purposes, the DSMB will perform 
expedited monitoring of all serious adverse events, perform ongoing monitoring of drop-outs 
and non- serious adverse events, determine whether study procedures should be changed or 
the study should be halted for reasons related to the safety of study subjects.
This protocol’s DSMB consists of 4 members:
The DSMB includes Connor Liston MD/PhD from Cornell (chair), Martin Keller MD from 
Brown, Sam Wilkerson MD from Yale, and Charles Green PhD (statistician) U. of Texas at 
Houston
The study team will provide the DSMB with reports biannually containing the following 
information for review:
●
Summary of overall study progress
●
Subject enrollment, treatment retention and dropout
●
Serious adverse events (SAEs)
●
Non-serious adverse events (AEs)
As highlighted in the SAE section of this MOP, expedited review will occur for all SAEs by 
the DSMB in addition to the regular biannual review/meeting. The study team must report the 
SAE within 48 hours of obtaining knowledge of the SAE. Further details are explained in the 
SAE section of this MOP.
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