Ketamine + Buprenorphine for Depression

(AFSP Trial)

Overseen By Nolan Williams

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Stanford University

Must be taking: SSRI, SNRI

Must not be taking: Opiates, Lamotrigine

Disqualifiers: Substance use disorder, Schizophrenia, Eating disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether combining ketamine (an anesthetic and antidepressant) with buprenorphine (a medication used for pain relief and opioid addiction treatment) provides faster and longer-lasting relief from suicidal thoughts in people with depression compared to ketamine and a placebo (inactive treatment). The focus is on individuals diagnosed with Major Depressive Disorder or Bipolar-II Disorder who are experiencing ongoing major depressive episodes. Participants should not have responded well to past antidepressant treatments. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for depression.

Do I need to stop my current medications to join the trial?

You must be on a stable dose of an SSRI or SNRI antidepressant for at least 4 weeks before joining the trial. If you are currently using lamotrigine, you need to stop it before receiving ketamine. Other medications are not specifically mentioned, so consult with the trial team for more details.

Will I have to stop taking my current medications?

The trial requires participants to be on a stable dose of an SSRI or SNRI antidepressant for at least 4 weeks before joining. If you are taking lamotrigine, you must stop it before receiving ketamine. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ketamine is generally safe as an FDA-approved anesthetic, though it can cause side effects. Administering it too quickly or in large amounts may slow breathing, so careful monitoring remains crucial.

Studies have found that buprenorphine is safe when used as directed, often for treating opioid addiction. However, it can cause side effects such as drowsiness, low blood pressure, and changes in heart rhythm. Combining it with other brain-affecting drugs, like benzodiazepines, can increase risks, including breathing problems.

Both treatments have been used in various settings, enhancing understanding of their safety. Nonetheless, monitoring remains important to manage any possible side effects effectively. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard antidepressant medications, which often take weeks to show effectiveness, ketamine has the potential to offer rapid relief from depressive symptoms, sometimes within hours. Researchers are excited about ketamine because it works through a different mechanism, targeting the NMDA receptors in the brain rather than the typical serotonin or norepinephrine pathways. Additionally, buprenorphine, typically used for pain relief and opioid addiction, is being tested for its potential antidepressant effects, which could offer a new avenue for treatment when combined with ketamine. This combination might provide a powerful alternative for those who have not responded to traditional therapies.

What evidence suggests that this trial's treatments could be effective for depression?

Research shows that ketamine, which participants in this trial may receive, can greatly improve depression symptoms. Studies indicate that after ketamine treatment, symptoms of depression and anxiety often improve within two weeks and can remain better for up to a month. One study found that about 45% of people responded well to ketamine, with 30% experiencing complete relief from their symptoms.

Buprenorphine, another treatment option in this trial, might also help with depression, though its effects appear smaller. Some research suggests it can slightly improve depression symptoms, with one study showing a noticeable drop in depression scores among participants. Together, these treatments may offer a promising way to manage depression symptoms. ^{6 7 8 9 10}

Who Is on the Research Team?

Alan F. Schatzberg

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

Adults aged 18-70 with Major Depressive Disorder currently in a depressive episode of at least 8 weeks, who haven't responded well to two different antidepressants for this episode. They must be generally healthy and women must use effective birth control or be non-childbearing. People with certain physical conditions, drug abuse history, or other mental health disorders are excluded.

Inclusion Criteria

You meet the threshold on the total SSI score of >/=11 at both screening and baseline visits.

I am either not able to have children or am using effective birth control.

Your body mass index (BMI), which is a measure of your body fat based on your weight and height, should be between 17 and 35.

Exclusion Criteria

You have a condition that affects your memory or thinking, such as dementia or delirium.

You have had an eating disorder such as anorexia, bulimia, or other similar disorders within the past five years.

You cannot participate in this study if you have taken part in another research study that involves a new drug or device in the past month or at the same time as this study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Ketamine Infusion

Participants receive a single infusion of ketamine at 0.5mg/kg IV over 40 minutes

1 day

1 visit (in-person)

Buprenorphine or Placebo Treatment

Participants receive either buprenorphine or placebo once daily

4 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Buprenorphine
• Ketamine
• Placebo oral tablet

Trial Overview The study is testing if ketamine followed by buprenorphine is more effective than ketamine followed by a placebo in reducing suicidal thoughts quickly and for an extended period. Participants will receive intravenous infusions over approximately 2.5 years.

How Is the Trial Designed?

Group I: Ketamine Experimental Treatment 1 Intervention

Every eligible participant will receive 0.5mg/kg IV given over 40 minutes

Group II: Buprenorphine or Placebo Active Control 2 Interventions

Buprenorphine or placebo once daily for 4 weeks

Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in European Union as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in United States as Spravato for:

• Treatment-resistant depression

Approved in European Union as Spravato for:

• Treatment-resistant depression

Approved in Canada as Spravato for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Published Research Related to This Trial

Subcutaneous (SC) administration of racemic ketamine and esketamine has shown rapid and robust antidepressant effects in both unipolar and bipolar patients, with response and remission rates ranging from 50% to 100% after single or multiple doses.

The studies indicated that SC ketamine is generally well-tolerated, with only transitory side effects, making it a promising and cost-effective treatment option for depression, especially in developing countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. Cavenaghi, VB., da Costa, LP., Lacerda, ALT., et al.[2021]

This systematic review analyzed 60 studies on the safety of ketamine for treating depression, revealing that acute doses of ketamine led to more frequent side effects, including psychiatric and cardiovascular issues, compared to placebo.

There is a notable lack of data on the long-term safety and effects of repeated ketamine dosing, highlighting the need for large-scale clinical trials to better understand its safety profile over extended use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Side-effects associated with ketamine use in depression: a systematic review. Short, B., Fong, J., Galvez, V., et al.[2019]

Ketamine and esketamine demonstrate rapid antidepressant effects, with improvements in clinical response observed within 40 minutes to 1 week for ketamine and 2 hours to 4 weeks for esketamine, along with reductions in depression scores and suicidality.

Despite their effectiveness, the long-term safety and efficacy of ketamine and esketamine remain uncertain, and the overall quality of the studies reviewed was critically low, highlighting the need for more rigorous research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. Lima, TM., Visacri, MB., Aguiar, PM.[2022]

Oral ketamine is a potentially safe and effective treatment for depression, but it requires higher doses (2.0-2.5 mg/kg) compared to intravenous administration due to lower systemic absorption (20%-25%).

Despite its promise as a more accessible and affordable option for treatment, the current literature on oral ketamine is limited, and further research is needed to understand its pharmacokinetics, safety, and efficacy compared to other administration routes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 2: Practical Considerations. Andrade, C.[2020]

In a study of 9016 patients receiving ketamine intravenous therapy (KIT) for depression, 53.6% showed a significant response (≥50% reduction in depression scores) within 14-31 days, indicating KIT's efficacy in real-world settings.

While most patients benefited from KIT, a small percentage (8.4%) experienced worsening depressive symptoms, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. McInnes, LA., Qian, JJ., Gargeya, RS., et al.[2023]

Oral ketamine has shown effectiveness in treating severe depression, including treatment-resistant cases and those with suicidal ideation, based on various studies including randomized controlled trials with doses ranging from 0.25 to 7 mg/kg.

Despite its lower bioavailability (20%-25% reaching the bloodstream), oral ketamine is well tolerated and can be adjusted for individual needs, making it a practical option for depression treatment alongside conventional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. Andrade, C.[2019]

A case study of a patient with treatment-resistant depression and active suicidal ideations showed that intravenous ketamine significantly reduced suicidal thoughts, even while the patient was on Buprenorphine, an opioid partial agonist.

This suggests that ketamine's antisuicidal effects may not solely rely on opioid mechanisms, indicating its potential safety and efficacy for individuals with substance use disorders or chronic pain who are maintained on opioid treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine's rapid antisuicidal effects are not attenuated by Buprenorphine. Hosanagar, A., Schmale, A., LeBlanc, A.[2021]

Intranasal ketamine (INK) significantly increased pain thresholds and reduced pain responses in mice, indicating its effective antinociceptive properties, regardless of the dose used.

The study found that INK is behaviorally and neurophysiologically safe, with no significant impact on anxiety-like behaviors or vital signs, although it did cause mild sedation and increased stereotypic movements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intranasal Ketamine for Acute Pain: Behavioral and Neurophysiological Safety Analysis in Mice. Goswami, N., Aleem, M., Manda, K.[2022]

Ketamine has been shown to have antidepressant effects in palliative care patients, with all 11 studies reviewed reporting positive outcomes, including one randomized controlled trial (RCT).

While ketamine may be effective for treating depression, its efficacy for physical pain relief is less clear, with recent RCTs indicating no significant analgesic effect, although some patients did experience pain relief with specific administration methods like epidural or intrathecal ketamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of Ketamine in the Palliative Care Setting: A Comprehensive Review of the Literature. Goldman, N., Frankenthaler, M., Klepacz, L.[2020]

There is currently no standardized safety monitoring protocol for off-label use of generic ketamine, and safety monitoring for intranasal esketamine varies by jurisdiction, leading to potential gaps in patient safety.

The Ketamine Side Effect Tool (KSET) is recommended as a comprehensive tool for monitoring both acute and long-term side effects of ketamine and esketamine treatments, addressing the lack of agreed frameworks for safety monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. Bayes, A., Short, B., Zarate, CA., et al.[2023]

A Phase I study involving 32 patients showed that esketamine (0.5 mg/kg) is generally safe and well-tolerated for use in painless gastroscopy, with no serious adverse events reported.

Esketamine resulted in a shorter recovery time compared to racemic ketamine (9 minutes vs. 13 minutes), making it a potentially more efficient option for anesthesia without gender differences affecting its pharmacokinetics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Safety of Esketamine in Chinese Patients Undergoing Painless Gastroscopy in Comparison with Ketamine: A Randomized, Open-Label Clinical Study. Wang, J., Huang, J., Yang, S., et al.[2022]

A 49-year-old woman with severe treatment-resistant major depression experienced significant improvement after receiving 36 sessions of ketamine intravenous therapy over 10 months, resulting in nearly a 50% reduction in her depressive symptoms.

The case suggests that long-term repeated ketamine therapy could be a viable option for patients with treatment-resistant depression, but further research is needed to determine the best treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketamine infusion for a patient with treatment-resistant major depression: a 10-month follow-up. Kwon, JH., Sim, WS., Hong, JP., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10970042/

Therapeutic Potential of Buprenorphine in Depression The results of our study suggest that buprenorphine may have the potential to improve depressive symptoms. Buprenorphine's therapeutic potential ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10149594/

The efficacy and safety of buprenorphine for the treatment ... Buprenorphine had a small effect on depressive symptoms (Hedges' g 0.17, 95%CI: 0.05 – 0.29). Results were driven by six trials of buprenorphine/samidorphan (N= ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0022395623001565

The efficacy and safety of buprenorphine for the treatment ... Conclusion. Buprenorphine may have a small benefit on depressive symptoms in patients with moderate or treatment resistant depression. Future studies should ...

4. frontierspartnerships.org frontierspartnerships.org/journals/advances-in-drug-and-alcohol-research/articles/10.3389/adar.2022.10254/full

Buprenorphine as a Treatment for Major Depression and ... All six patients experienced a significant improvement in depressive symptoms, with the average HAM-D rating falling from 22.8 to 6.0 and the ...

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2779751

Patient-Reported Outcomes of Treatment of Opioid ... For the primary outcome measure of TSQM Global Satisfaction Score, the mean (SD) at baseline was 71.2 (18.0) in the depot buprenorphine group ...

6. brixadihcp.com brixadihcp.com/safety/

Clinical Safety Profile The safety of BRIXADI was evaluated in 440 opioid-dependent patients across 2 phase 3 clinical studies: one double-blind, active-control (N=213) and one ...

7. brixadi.com brixadi.com/pdfs/brixadi-prescribing-information.pdf

HIGHLIGHTS OF PRESCRIBING INFORMATION ... Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including respiratory depression, overdose ...

8. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK459126/

Buprenorphine - StatPearls - NCBI Bookshelf Buprenorphine exerts some anticholinergic-like effects and may cause CNS depression, hypotension, QT prolongation, and lower seizure threshold.

9. samhsa.gov samhsa.gov/substance-use/treatment/options/buprenorphine

What is Buprenorphine? Side Effects, Treatment & Use When taken as prescribed, buprenorphine is safe and effective. Buprenorphine has unique pharmacological properties that: Diminish the effects of ...

10. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/210136Orig1s000lbl.pdf

Approval [Rx ONLY] - accessdata.fda.gov Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including respiratory ...