Ketamine for Depression

Overseen By Carlos A Zarate, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Mental Health (NIMH)

Must not be taking: Opioids, MAOIs, Fluoxetine, Aripiprazole

Disqualifiers: Psychotic disorders, Substance abuse, Serious illnesses, others

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

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

Compensation: Varies

Number of Visits: 3

70 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Most drugs that treat mood disorders take a long time to work. Ketamine works within hours. A dose can last for a week or more. Certain receptors in the brain might help ketamine work. A drug that blocks these receptors might affect how it works. Objective: To see if the antidepressant response of ketamine is linked to AMPA receptors. Eligibility: Adults ages 18-70 with major depression disorder without psychotic features Design: Participants will be screened under protocol 01-M-0254. They will have blood tests and a physical exam. Participants will stay at the NIH Clinical Center for 5 weeks. Phase 1 lasts 4 weeks. For 2 weeks, participants will taper off their psychiatric medicine. Then they will have the following tests: * Blood draws * Psychological tests * MRI: Participants will lie in a machine that takes pictures of their brain. * MEG: Participants will lie down and do tasks. A cone lowered on their head will record brain activity. * Optional sleep tests: Electrodes on the scalp and body and belts around the body will monitor participants while they sleep. * Optional TMS: Participants will do tasks while a wire coil is held on their scalp. An electrical current will pass through the coil that affects brain activity. For phase 2, on day 0 participants will take the study drug or a placebo orally. While having a MEG, they will get ketamine infused into a vein in one arm while blood is drawn from a vein in the other arm. On day 1, participants will again take the study drug or a placebo orally. On days 3-7, they will repeat many of the phase 1 tests. Days 8 and 9 are optional and include an open label ketamine treatment and many of the phase 1 tests.

Will I have to stop taking my current medications?

Yes, participants will need to taper off their psychiatric medications during the first 2 weeks of the trial. Additionally, treatment with any non-psychiatric medications is not allowed prior to entering Phase II.

What data supports the effectiveness of the drug Ketamine for treating depression?

Research shows that intravenous ketamine can quickly and significantly improve depression symptoms, even in patients who haven't responded to other treatments. Studies have demonstrated its rapid antidepressant effects, providing relief for about 2-3 weeks after treatment. ^{1 2 3 4 5}

Is ketamine safe for treating depression?

Ketamine has been shown to have rapid antidepressant effects, but common side effects include a sense of detachment from reality and increased blood pressure. These side effects are generally temporary, and the treatment is considered promising with good tolerability. ^{6 7 8 9 10}

How is the drug ketamine unique in treating depression?

Ketamine is unique in treating depression because it can produce rapid antidepressant effects, often within hours, and can be administered subcutaneously (under the skin), which is convenient and cost-effective, especially in developing countries. This route of administration is as effective as intravenous methods and may be safer, offering a promising alternative for patients with depression. ^{2 6 11 12 13}

Research Team

Carlos A Zarate, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Eligibility Criteria

Adults aged 18-70 with major depressive disorder without psychotic features, who haven't responded to two antidepressant trials. They must be willing to stay at the NIH Clinical Center for 5 weeks and agree to tests like blood draws, MRI, MEG, and possibly sleep tests or TMS. Women able to get pregnant should use birth control or abstain from sex.

Inclusion Criteria

Individuals who are able to get pregnant must be willing to remain sexually abstinent or use at least one form of effective birth control during participation in Phase III.

My trial is in an early phase (I or II).

Subjects must fulfill DSM-IV or -5criteria for Major Depression (Major Depressive Disorder) without psychotic features, based on clinical assessment and informed by a structured diagnostic interview (SCID-P).

Exclusion Criteria

I am taking medication that is not for mental health issues.

A current NIMH employee/staff or their immediate family member

Pregnant or nursing individuals or those who are physically able to become pregnant. Participants who are physically able to become pregnant or cause a pregnancy must use at least one form of effective birth control or remain completely abstinent from sexual intercourse during the entire period of study participation (or until the last clinical labs and ratings). Participants able to become pregnant must have negative urine pregnancy tests no more than 24 hours prior to receiving the study drugs and undergoing imaging procedures

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase 1

Participants taper off psychiatric medication and undergo baseline testing including blood draws, psychological tests, MRI, MEG, and optional sleep tests and TMS

4 weeks

Multiple visits (in-person)

Phase 2

Participants receive open-label ketamine infusion with randomized, double-blind add-on intervention (perampanel vs. placebo) and repeat many of the Phase 1 tests

1 week

Daily visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including mood symptoms and side effects assessment

1-2 weeks

2 visits (in-person)

Treatment Details

Interventions

• Ketamine

Trial Overview The trial is testing if ketamine's rapid antidepressant effects are related to AMPA receptors in the brain. Participants will stop taking current psychiatric meds, undergo various tests including brain imaging, then receive either a study drug or placebo orally before getting an intravenous ketamine infusion while their brain activity is monitored.

Participant Groups

Group I: 3 Experimental Treatment 2 Interventions

Individuals in Arm 3 will receive double-blinded placebo and open-label ketamine on the first day, then double-blinded placebo on the second day.

Group II: 2 Experimental Treatment 4 Interventions

Individuals in Arm 2 will receive double-blinded placebo and open-label ketamine on the first day, then double-blinded perampanel on the second day.

Group III: 1 Experimental Treatment 3 Interventions

Individuals in Arm 1 will receive double-blinded perampanel and open-label ketamine on the first day, then double-blinded perampanel on the second day.

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?

National Institute of Mental Health (NIMH)

Lead Sponsor

Trials

3,007

Recruited

2,852,000+

Findings from Research

In a European clinical trial, a 55-year-old male with treatment-resistant depression and substance use disorder showed significant improvement in depression symptoms after a single intravenous infusion of ketamine, with reductions in Hamilton Depression Rating Scale (HDRS) scores from 36 to 16 and Beck Depression Inventory (BDI) scores from 26 to 9.

The antidepressant effects of ketamine were rapid, with the patient reporting improvements just 25 minutes into the infusion, and these effects lasted for at least 7 days, demonstrating ketamine's potential as a fast-acting treatment for depression even in patients with co-occurring substance use disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketamine therapy in a patient with a treatment-resistant major depression. Liebrenz, M., Borgeat, A., Leisinger, R., 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]

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]

Intravenous ketamine has been shown to be safe and effective in rapidly reducing depressive symptoms, including suicidal thoughts, in patients with treatment-resistant unipolar or bipolar depression, based on five controlled studies and additional open-label studies.

While ketamine shows promise as a short-term antidepressant therapy, further research is needed to assess its long-term safety and effectiveness, as well as the efficacy of alternative administration routes like oral or intranasal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for the treatment of depression. Howland, RH.[2022]

Racemic ketamine and its derivative, S-ketamine, have been shown to provide rapid relief from depressive symptoms, with effects lasting approximately 2-3 weeks after treatment, based on multiple clinical trials.

Further research is needed to optimize dosing strategies, especially for specific populations like obese individuals, and to monitor long-term safety regarding cognitive and organ system effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Key considerations for the use of ketamine and esketamine for the treatment of depression: focusing on administration, safety, and tolerability. Kritzer, MD., Pae, CU., Masand, PS.[2023]

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]

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 review of 41 treatment arms from 21 studies found that ketamine formulations that maximize first pass metabolism and delay the time to peak concentration (Tmax) are associated with better safety and tolerability, particularly in reducing side effects like dissociation and increased blood pressure.

The study revealed strong correlations between the ketamine:norketamine ratio and both dissociation ratings and blood pressure changes, suggesting that careful formulation can help minimize adverse effects while maintaining the antidepressant efficacy of ketamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. Glue, P., Russell, B., Medlicott, NJ.[2021]

Subanaesthetic doses of ketamine have shown substantial efficacy in treating depression, with response rates averaging 77% and remission rates around 43% within 4 to 72 hours after a single dose.

Despite the rapid improvement in mood for many patients, the effects are often short-lived, highlighting the need for further research on dosing regimens and strategies to maintain the antidepressant response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. Katalinic, N., Lai, R., Somogyi, A., et al.[2013]

A 65-year-old male cancer patient experienced significant improvement in depression symptoms and achieved remission within 7 days after receiving subcutaneous esketamine, indicating its rapid antidepressant effect.

Subcutaneous administration of esketamine appears to be a safe and effective option for managing both pain and depression in palliative care, suggesting it could be a valuable alternative to traditional intravenous methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repeated subcutaneous esketamine administration for depressive symptoms and pain relief in a terminally ill cancer patient: A case report. Barbosa, MG., Delfino, RS., Sarin, LM., et al.[2021]

In a study involving 156 participants with suicidal ideation, ketamine treatment led to a significantly higher rate of full remission of suicidal thoughts at day 3 compared to placebo, with 63% of those receiving ketamine achieving remission versus 31.6% in the placebo group.

The study found that ketamine was safe in the short term, with limited side effects and no occurrences of manic or psychotic symptoms, suggesting it could be a rapid and effective option for acute care in suicidal patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. Abbar, M., Demattei, C., El-Hage, W., et al.[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]

References

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

Intravenous ketamine therapy in a patient with a treatment-resistant major depression. [2022]

2. England pubmed.ncbi.nlm.nih.gov

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

3. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Ketamine for the treatment of depression. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Key considerations for the use of ketamine and esketamine for the treatment of depression: focusing on administration, safety, and tolerability. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

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

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. Germany pubmed.ncbi.nlm.nih.gov

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. [2013]

11. England pubmed.ncbi.nlm.nih.gov

Repeated subcutaneous esketamine administration for depressive symptoms and pain relief in a terminally ill cancer patient: A case report. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. [2022]

13. 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]