Major Depressive DisorderPhase 3AFSPNCT04116528
Opiate Suicide Study in Patients With Major Depression
A Phase 3 study testing Buprenorphine in people with Major Depressive Disorder, run by Stanford University at 1 site in United States.
Trial summary
To explore whether intravenous ketamine followed by buprenorphine produces more rapid and sustained anti-suicidal effects than ketamine followed by placebo, investigators will conduct a single study that will take approximately 2.5 years to complete. 60 subjects (60 infusions) or approximately 24 infusions per year. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Buprenorphine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 50 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Aug 2020to 28 Apr 2025
- Phase
- Phase 3
- 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 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- A subject will be eligible for inclusion only if all of the following criteria are met:
- Male or female, 18 to 70 years of age, inclusive, at screen.
- Able to read, understand, and provide written, dated informed consent prior to screening. Participants will be deemed likely to comply with study protocol and communicate with study personnel about adverse events and other clinically important information.
- Diagnosed with Major Depressive Disorder (MDD), single or recurrent or Bipolar-II Disorder and currently experiencing a Major Depressive Episode (MDE) of at least eight weeks in duration, prior to screening, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision(DSM-IV-TR™). The diagnosis of MDD will be made by a site psychiatrist and supported by the Structured Clinical Interview for DSM-IV-TR™ (SCID-I/P).
- Has a history of TRD during the current MDE, as assessed by the investigator. TRD is defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms), as perceived by the participant, to at least one "treatment course" of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration. The adequacy of dose and duration of the antidepressant therapy will be determined as per the MGH ATRQ criteria. Participants must currently be on a stable (for at least 4 weeks) and adequate (according to the MGH ATRQ) dose of ongoing SSRI or SNRI antidepressant therapy, of which total duration must be at least 8 weeks. Participants may also have a history of intolerance to at least 2 antidepressant medications. These patients with the intolerance history will not be required to be currently taking an antidepressant medication.
- Meet the threshold on the total SSI score of >/=6 at screening visit.
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- Participants must qualify as "Moderately Treatment Refractory" using the Maudsley staging method, which incorporates past treatments, severity of symptoms and duration of presenting episode.
- In good general health, as ascertained by medical history, physical examination (PE) (including measurement of supine and standing vital signs), clinical laboratory evaluations, and 3-lead electrocardiogram (ECG) if no evaluation available from the last 6 months.
- If female, a status of non-childbearing potential or use of an acceptable form of birth control per the following specific criteria:
- Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., permanently sterilized (status post hysterectomy, bilateral tubal ligation), or is post-menopausal with her last menses at least one year prior to screening); or b. Childbearing potential, and meets the following criteria: i. Childbearing potential, including women using any form of hormonal birth control, on hormone replacement therapy started prior to 12 months of amenorrhea, using an intrauterine device (IUD), having a monogamous relationship with a partner who has had a vasectomy, or is sexually abstinent.
- Negative urinary pregnancy test at screening, confirmed by a negative urinary pregnancy test at randomization prior to receiving study treatment.
- Willing and able to continuously use one of the following methods of birth control during the course of the study, defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly: implants, injectable or patch hormonal contraception, oral contraceptives, IUD, double-barrier contraception, sexual abstinence. The form of birth control will be documented at screening and baseline.
- Body mass index between 17-40kg/m2.
- Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive behavioral, insight-oriented, et al) and frequency (e.g., weekly or monthly) of the therapy has been stable for at least three months prior to screening and if the type and frequency of the therapy is expected to remain stable during the course of the subject's participation in the study.
- Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, or trazodone) will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject's participation in the study.
Who cannot join
- A potential participant will NOT be eligible for participation in this study if any of the following criteria are met:
- Female of childbearing potential who is not willing to use one of the specified forms of birth control during the study.
- Female that is pregnant or breastfeeding.
- Female with a positive pregnancy test at screening or baseline.
- Total SSI score of <6 at the screening visit.
- 6. Current diagnosis of a Substance Use Disorder (Abuse or Dependence, as defined by DSM-IV-TR™), with the exception of nicotine dependence, at screening or within six months prior to screening.
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- 7. Current diagnosis of Axis I disorders other than Dysthymic Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder, Agoraphobia, or Specific Phobia (unless one of these is comorbid and clinically unstable, and/or the focus of the participant's treatment for the past six months or more).
- 8. History of schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes.
- 9. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified, within one year of screening.
- 10. Any Axis I or Axis II Disorder, which at screening is clinically predominant to their MDD or has been predominant to their MDD at any time within six months prior to screening. A diagnosis of borderline personality disorder is excluded.
- 11. In the judgment of the investigator, the subject is at significant risk for suicidal behavior during the course of his/her participation in the study.
- 12. Has dementia, delirium, amnestic, or any other cognitive disorder.
- 13. Has a clinically significant abnormality on the screening physical examination that might affect safety, study participation, or confound interpretation of study results.
- 14. Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation.
- 15. Known history or current episode of:
- QTcF (Fridericia-corrected) ≥450 msec at screening (Visit 1) or randomization
- Syncopal event within the past year.
- Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2
- Angina pectoris
- Heart rate <50 or >105 beats per minute at screening or randomization
- 16. Chronic lung disease.
- 17. Lifetime history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system disorder (e.g., Alzheimer's or Parkinson's Disease), epilepsy, mental retardation, or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system (CNS), or a history of significant head trauma within the past two years.
- 18. Presents with any of the following lab abnormalities w/in the past 6 months:
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- Thyroid stimulating hormone (TSH) outside of the normal limits and clinically significant as determined by the investigator. Free thyroxine (T4) levels may be measured if TSH level is high. Subject will be excluded if T4 level is clinically significant.
- Any other clinically significant abnormal laboratory result at the time of the screening exam.
- 19. History of hypothyroidism and has been on a stable dosage of thyroid replacement medication for less than six months prior to screening.(Subjects on a stable dosage of thyroid replacement medication for at least six months or more prior to screening are eligible for enrollment.)
- 20. History of hyperthyroidism which was treated (medically or surgically) less than six months prior to screening.
- 21. Any current or past history of any physical condition which in the investigator's opinion might put the subject at risk or interfere with study results interpretation.
- 22. History of positive screening urine test for drugs of abuse at screening: cocaine, amphetamines, barbiturates, opiates.
- 23. Current (or chronic) use of opiates. History of Opioid Use Disorder.
- 24. Current use of lamotrigine and an inability to stop the medication prior to receiving ketamine.
Trial locations and contacts
1 site in 1 country.
United States1 site
Stanford University School of Medicine
Stanford, California, 94305
About this study
To explore whether intravenous ketamine followed by buprenorphine produces more rapid and sustained anti-suicidal effects than ketamine followed by placebo, investigators will conduct a single study that will take approximately 2.5 years to complete. 60 subjects (60 infusions) or approximately 24 infusions per year.
Read the detailed description
The investigators hypothesize that patients who receive buprenorphine following ketamine will demonstrate significantly greater anti-suicidal effects over the course of the study and maintained until four weeks of buprenorphine than will placebo. Buprenorphine subjects will also demonstrate longer times to recurrence than will those who receive ketamine followed by placebo. As secondary analyses, the investigators will test whether there is a relationship of improvement in sleep and pain to change in suicide ratings.
Aim 2: To assess the potential role played by the opioid properties of a single infusion of ketamine, investigators will for the ketamine portion determine ketamine and metabolite blood levels during and after the infusion as well as pupillary changes and correlate them to anti-suicidal response at Day 1. Investigators will also collect blood to determine buprenorphine blood levels, prolactin as well as collecting data on pupillary changes and then assess for potential relationships with anti-suicidal response.
- Conditions
- Major Depressive Disorder
- Being tested
- Buprenorphine, Placebo
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BuprenorphineDrug
Sublingual troches of buprenorphine at doses from 0.2 to 0.8 mg per day (1-4 per day)
PlaceboDrug
Sublingual troches of placebo (1-4 per day)
| Study group | Role | What they receive |
|---|---|---|
| Buprenorphine after ketamine | Active comparator | Patients will be randomized to receive buprenorphine or placebo under double blind, random assignment conditions for 4 weeks. Prior to starting the comparison all subjects first receive an iv infusion of ketamine. Receives: Drug: Buprenorphine |
| Placebo after ketamine | Placebo comparator | Patients will be randomized to receive buprenorphine or placebo under double blind, random assignment conditions for 4 weeks. Prior to starting the comparison all subjects first receive an iv infusion of ketamine. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Scale for Suicidal Ideation (SSI) Total Scores Will be Analyzed as the Primary Outcome Measure Using Mixed Effects Models,
Analyses included a modified intention-to-treat population, defined as all randomized participants who received one week of treatment and completed the week 1 assessment of buprenorphine or placebo. A linear mixed-effects model tested the primary hypothesis of efficacy, measured by change in SSI total scores. The model included random effects for patient and fixed effects for treatment group, time as a continuous variable (days of study: 1, 3, 10, 17, 24, 31), and the time-by-treatment group interaction, along with an unstructured covariance matrix. The SSI has 19 items, each scored 0-2, for a maximum of 38 points. Higher scores indicate worse suicidal ideation.
Measured: Day 1 and 31
Secondary outcomes (2)
MADRS Change Score
Montgomery-Åsberg Depression Rating Scale (MADRS) is a validated, 10-item rating scale with each item being scored on a scale from 0-6 with a total score ranging from 0-60. Lower scores indicate a decreased severity of depression.
Measured: Day 1 and 31
HAM-D Change Score
The Hamilton Depression Scale (HAM-D) is a validated rating scale which consists of 17 items. Nine of the items are scored on a scale of 0-4 and 8 items are scored on a scale of 0-2 for a total scoring range of 0-52. A score of 0-7 is generally accepted to be within the normal range (or in clinical remission), while a score of 20 or higher indicates increased severity of depression. In general, the lower the total score the less severe the depression.
Measured: Day 1 and 31
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Oct 2019
- Study start1 Aug 2020
- Primary completion28 Apr 2025
- Study completion28 Apr 2025
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 Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Alan Schatzberg, Stanford University
- Investigators
- Alan F. Schatzberg, Study director, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04116528
- Sponsor's protocol ID
- 51536
- Acronym
- AFSP
- Status last verified
- Apr 2026
- First submitted
- 3 Jul 2019
- Last updated
- 22 May 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Opiate Suicide Study in Patients With Major Depression
- ClinicalTrials.gov ID
- NCT04116528
- Acronym / sponsor ID
- AFSP / 51536
- Conditions
- Major Depressive Disorder
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Study start
- 1 Aug 2020 (actual)
- Primary completion
- 28 Apr 2025 (actual)
- Study completion
- 28 Apr 2025 (actual)
- First posted
- 4 Oct 2019 (actual)
- Results
- Posted 22 May 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To explore whether intravenous ketamine followed by buprenorphine produces more rapid and sustained anti-suicidal effects than ketamine followed by placebo, investigators will conduct a single study that will take approximately 2.5 years to complete. 60 subjects (60 infusions) or approximately 24 infusions per year.
Detailed description
The investigators hypothesize that patients who receive buprenorphine following ketamine will demonstrate significantly greater anti-suicidal effects over the course of the study and maintained until four weeks of buprenorphine than will placebo. Buprenorphine subjects will also demonstrate longer times to recurrence than will those who receive ketamine followed by placebo. As secondary analyses, the investigators will test whether there is a relationship of improvement in sleep and pain to change in suicide ratings.
Aim 2: To assess the potential role played by the opioid properties of a single infusion of ketamine, investigators will for the ketamine portion determine ketamine and metabolite blood levels during and after the infusion as well as pupillary changes and correlate them to anti-suicidal response at Day 1. Investigators will also collect blood to determine buprenorphine blood levels, prolactin as well as collecting data on pupillary changes and then assess for potential relationships with anti-suicidal response.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Buprenorphine after ketamine | Active comparator | Drug: BuprenorphinePatients will be randomized to receive buprenorphine or placebo under double blind, random assignment conditions for 4 weeks. Prior to starting the comparison all subjects first receive an iv infusion of ketamine. |
| Placebo after ketamine | Placebo comparator | Drug: PlaceboPatients will be randomized to receive buprenorphine or placebo under double blind, random assignment conditions for 4 weeks. Prior to starting the comparison all subjects first receive an iv infusion of ketamine. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- A subject will be eligible for inclusion only if all of the following criteria are met:
Key exclusion criteria (32 listed)
- A potential participant will NOT be eligible for participation in this study if any of the following criteria are met:
- 6. Current diagnosis of a Substance Use Disorder (Abuse or Dependence, as defined by DSM-IV-TR™), with the exception of nicotine dependence, at screening or within six months prior to screening.
- 7. Current diagnosis of Axis I disorders other than Dysthymic Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder, Agoraphobia, or Specific Phobia (unless one of these is comorbid and clinically unstable, and/or the focus of the participant's treatment for the past six months or more).
- 8. History of schizophrenia or schizoaffective disorders, or any history of psychotic symptoms in the current or previous depressive episodes.
- 9. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified, within one year of screening.
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 |
|---|---|---|
| BuprenorphineSublingual troches of buprenorphine at doses from 0.2 to 0.8 mg per day (1-4 per day) | Drug | Buprenorphine after ketamine |
| PlaceboSublingual troches of placebo (1-4 per day) | Drug | Placebo after ketamine |
Primary outcome
Change in Scale for Suicidal Ideation (SSI) Total Scores Will be Analyzed as the Primary Outcome Measure Using Mixed Effects Models,
Time frame: Day 1 and 31
Analyses included a modified intention-to-treat population, defined as all randomized participants who received one week of treatment and completed the week 1 assessment of buprenorphine or placebo. A linear mixed-effects model tested the primary hypothesis of efficacy, measured by change in SSI total scores. The model included random effects for patient and fixed effects for treatment group, time as a continuous variable (days of study: 1, 3, 10, 17, 24, 31), and the time-by-treatment group interaction, along with an unstructured covariance matrix. The SSI has 19 items, each scored 0-2, for a maximum of 38 points. Higher scores indicate worse suicidal ideation.
2 secondary outcomes
MADRS Change Score
Time frame: Day 1 and 31
HAM-D Change Score
Time frame: Day 1 and 31
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 May 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Alan F. Schatzberg study director
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Buprenorphine in people with Major Depressive Disorder, run by Stanford University at 1 site 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 15 inclusion and 32 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: finished, as of the sponsor's last update on 22 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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. Some participants in this study may receive a placebo. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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 22 May 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?
Change in Scale for Suicidal Ideation (SSI) Total Scores Will be Analyzed as the Primary Outcome Measure Using Mixed Effects Models, (time frame: Day 1 and 31). 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 22 May 2026.