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

60 Participants Needed

Trial Summary

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.

What data supports the idea that Ketamine + Buprenorphine for Depression is an effective drug?

The available research shows that ketamine, when used alone, has been effective in treating depression. For example, subcutaneous ketamine has shown a rapid and strong antidepressant effect, with response rates between 50% to 100% in various studies. Oral ketamine has also been found effective in treating severe depression and treatment-resistant depression, with similar outcomes to conventional antidepressants. However, there is no specific data provided on the combination of ketamine and buprenorphine for depression, so the effectiveness of this combination remains unclear based on the information available. ^{1 2 3 4 5}

What evidence supports the effectiveness of the drug Ketamine for depression?

Research shows that ketamine, when administered through various routes like oral, subcutaneous, and intravenous, can produce rapid and strong antidepressant effects. Studies have demonstrated that ketamine is effective in treating severe depression, depression with suicidal thoughts, and treatment-resistant depression, with response rates ranging from 50% to 100%. ^{1 2 3 4 5}

What safety data exists for ketamine and buprenorphine in treating depression?

Existing safety data for ketamine in treating depression includes findings from systematic reviews and clinical trials. Subcutaneous ketamine has shown rapid antidepressant effects with transitory side effects. The Ketamine Side Effect Tool (KSET) highlights the need for comprehensive safety monitoring. A systematic review identified psychiatric, cardiovascular, and neurological side effects, with a call for more research on long-term safety. However, specific safety data for the combination of ketamine and buprenorphine in depression is not detailed in the provided research. ^{1 6 7 8 9}

Is ketamine safe for treating depression?

Research shows that ketamine can have side effects like changes in mood, heart rate, and brain function, especially after repeated use. While it is generally considered safe for short-term use in treating depression, more studies are needed to understand its long-term safety. ^{1 6 7 8 9}

Is Ketamine a promising drug for depression?

Yes, Ketamine is a promising drug for depression. It acts quickly and effectively, showing strong antidepressant effects in various forms, including subcutaneous and oral administration. Studies have shown that it can help reduce depression symptoms and suicidal thoughts, making it a valuable option for those who haven't responded to other treatments. ^{1 2 10 11 12}

How is the drug Ketamine + Buprenorphine unique for treating depression?

The combination of Ketamine and Buprenorphine for depression is unique because Ketamine provides rapid antidepressant effects, even in treatment-resistant cases, while Buprenorphine, an opioid partial agonist, does not block these effects, suggesting non-opioid mechanisms are involved. This combination may be particularly beneficial for patients with substance use disorders or chronic pain, offering a novel approach to managing depression safely. ^{1 2 10 11 12}

What is the purpose of this trial?

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.

Research Team

Alan F. Schatzberg

Principal Investigator

Stanford University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Subcutaneous Ketamine in Depression: A Systematic Review. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

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

3. United States pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

Intravenous ketamine infusion for a patient with treatment-resistant major depression: a 10-month follow-up. [2018]

5. Netherlands pubmed.ncbi.nlm.nih.gov

A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Side-effects associated with ketamine use in depression: a systematic review. [2019]

7. Netherlands pubmed.ncbi.nlm.nih.gov

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses. [2022]

9. New Zealand 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. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Ketamine's rapid antisuicidal effects are not attenuated by Buprenorphine. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Intranasal Ketamine for Acute Pain: Behavioral and Neurophysiological Safety Analysis in Mice. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

The Efficacy of Ketamine in the Palliative Care Setting: A Comprehensive Review of the Literature. [2020]